[Frontiers in Bioscience, Landmark, 25, 1510-1537, March 1, 2020]

Evolution of PIKK family kinase inhibitors: A new age cancer therapeutics

Althaf Shaik1, Sivapriya Kirubakaran1

1Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India, 382355, Indian Institute of Technology Gandhinagar, Gujarat, India 382355


1. Abstract
2. Introduction
3. PIKK family of protein domain architecture
4. A brief introduction to PIKK family members
    4.1. mTOR kinase: a master regulator
    4.2. DNA-PK: A regulator of DNA DSBs repair by NHEJ mechanism
    4.3. ATM kinase and ATR kinase: DNA damage sensing and response
    4.4. hSMG1 kinase: a key regulator of non-sense mediated mRNA decay
5. Targeting PIKK kinases for cancer therapy
    5.1. Conserved kinase domains in PIKKs
    5.2. PIKK inhibitors
      5.2.1 Wortmannin
      5.2.2. Caffeine
      5.2.3. Schisandrin
      5.2.4. Rapalogs
      5.2.5. Benzopyran-4-one derivatives
      5.2.6. Thiaanthrenpyran-4-one
      5.2.7. Quinoline derivative’s as PIKK inhibitors
      5.2.8. Pyrazine derivatives
      5.2.9. Pyrimidine derivatives
6. Conclusions
7. Future perspective
8. Acknowledgments
9. References


Phosphatidylinositol-3 kinase-related kinases (PIKKs) belong to a family of atypical serine/threonine kinases in humans. They actively participate in a diverse set of cellular functions such as meiotic, V(D)J recombination, chromosome maintenance, DNA damage sensing and repair, cell cycle progression and arrest. ATR, ATM, DNA-PKcs, mTOR and hSMG are the members of the PIKK family that play an important role in in cancer cell proliferation, autophagy, and cell survival to radio and chemotherapy. Thereby targeting these PIKK kinases in cancer along with chemo/radiotherapy agents, can help in differential cytotoxicity towards cancer cell over the normal cell. In this review, we compile the various small molecule kinase inhibitors with respect to structural and strategic targeting of PIKK family members. Rapalogs, AZD8055, AZD2014, OSI-027, INK-128, MLN0128, VX970, NVP-BEZ235, Torin2, AZ20, and AZ31 are the diverse scaffolds which have successfully made into the pre-clinical trials either as mono or combinatorial therapy for the treatment of various human cancers. Their synthesis and pre-clinical trial highlight the challenges associated in the development process.


1. T. Hunter: When is a lipid kinase not a lipid kinase? When it is a protein kinase. Cell, 83(1), 1-4 (1995)
DOI: 10.1016/0092-8674(95)90225-2

2. V. A. Zakian: ATM-related genes: what do they tell us about functions of the human gene? Cell, 82(5), 685-7 (1995)
DOI: 10.1016/0092-8674(95)90463-8

3. K. A. Cimprich and D. Cortez: ATR: an essential regulator of genome integrity. Nature Reviews Molecular Cell Biology, 9, 616 (2008)
DOI: 10.1038/nrm2450

4. H. Yang, D. G. Rudge, J. D. Koos, B. Vaidialingam, H. J. Yang and N. P. Pavletich: mTOR kinase structure, mechanism and regulation. Nature, 497, 217 (2013)
DOI: 10.1038/nature12122

5. S. B. McMahon, H. A. Van Buskirk, K. A. Dugan, T. D. Copeland and M. D. Cole: The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell, 94(3), 363-74 (1998)
DOI: 10.1016/S0092-8674(00)81479-8

6. A. Saleh, D. Schieltz, N. Ting, S. B. McMahon, D. W. Litchfield, J. R. Yates, 3rd, S. P. Lees-Miller, M. D. Cole and C. J. Brandl: Tra1p is a component of the yeast Ada.Spt transcriptional regulatory complexes. J Biol Chem, 273(41), 26559-65 (1998)
DOI: 10.1074/jbc.273.41.26559

7. A. Yamashita, T. Ohnishi, I. Kashima, Y. Taya and S. Ohno: Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev, 15(17), 2215-28 (2001)
DOI: 10.1101/gad.913001

8. Y. Shiloh: ATM and ATR: networking cellular responses to DNA damage. Curr Opin Genet Dev, 11(1), 71-7 (2001)
DOI: 10.1016/S0959-437X(00)00159-3

9. K. K. Khanna and S. P. Jackson: DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet, 27(3), 247-54 (2001)
DOI: 10.1038/85798

10. G. C. Smith and S. P. Jackson: The DNA-dependent protein kinase. Genes Dev, 13(8), 916-34 (1999)
DOI: 10.1101/gad.13.8.916

11. Y. Ziv, A. Bar-Shira, I. Pecker, P. Russell, T. J. Jorgensen, I. Tsarfati and Y. Shiloh: Recombinant ATM protein complements the cellular A-T phenotype. Oncogene, 15(2), 159-67 (1997)
DOI: 10.1038/sj.onc.1201319

12. C. T. Keith and S. L. Schreiber: PIK-Related Kinases: DNA Repair, Recombination, and Cell Cycle Checkpoints. Science, 270(5233), 50 (1995)
DOI: 10.1126/science.270.5233.50

13. S. Imseng, C. H. S. Aylett and T. Maier: Architecture and activation of phosphatidylinositol 3-kinase related kinases. Current Opinion in Structural Biology, 49, 177-189 (2018)
DOI: 10.1016/j.sbi.2018.03.010

14. R. Bosotti, A. Isacchi and E. L. Sonnhammer: FAT: a novel domain in PIK-related kinases. Trends Biochem Sci, 25(5), 225-7 (2000)
DOI: 10.1016/S0968-0004(00)01563-2

15. X. Chen, R. Zhao, G. G. Glick and D. Cortez: Function of the ATR N-terminal domain revealed by an ATM/ATR chimera. Exp Cell Res, 313(8), 1667-74 (2007)
DOI: 10.1016/j.yexcr.2007.02.015

16. D. A. Mordes, G. G. Glick, R. Zhao and D. Cortez: TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev, 22(11), 1478-89 (2008)
DOI: 10.1101/gad.1666208

17. T. Schmelzle and M. N. Hall: TOR, a central controller of cell growth. Cell, 103(2), 253-62 (2000)
DOI: 10.1016/S0092-8674(00)00117-3

18. M. I. Chiu, H. Katz and V. Berlin: RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proceedings of the National Academy of Sciences, 91(26), 12574 (1994)
DOI: 10.1073/pnas.91.26.12574

19. D. M. Sabatini, H. Erdjument-Bromage, M. Lui, P. Tempst and S. H. Snyder: RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell, 78(1), 35-43 (1994)
DOI: 10.1016/0092-8674(94)90570-3

20. E. J. Brown, M. W. Albers, T. Bum Shin, K. ichikawa, C. T. Keith, W. S. Lane and S. L. Schreiber: A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature, 369(6483), 756-758 (1994)
DOI: 10.1038/369756a0

21. K. Hara, Y. Maruki, X. Long, K. Yoshino, N. Oshiro, S. Hidayat, C. Tokunaga, J. Avruch and K. Yonezawa: Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell, 110(2), 177-89 (2002)
DOI: 10.1016/S0092-8674(02)00833-4

22. D. S. Dos, S. M. Ali, D.-H. Kim, D. A. Guertin, R. R. Latek, H. Erdjument-Bromage, P. Tempst and D. M. Sabatini: Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton. Current Biology, 14(14), 1296-1302 (2004)
DOI: 10.1016/j.cub.2004.06.054

23. R. Zoncu, A. Efeyan and D. M. Sabatini: mTOR: from growth signal integration to cancer, diabetes and ageing. Nature reviews. Molecular cell biology, 12(1), 21-35 (2011)
DOI: 10.1038/nrm3025

24. S. V. Bhagwat and A. P. Crew: Novel inhibitors of mTORC1 and mTORC2. Curr Opin Investig Drugs, 11(6), 638-45 (2010)

25. X. M. Ma and J. Blenis: Molecular mechanisms of mTOR-mediated translational control. Nature Reviews Molecular Cell Biology, 10, 307 (2009)
DOI: 10.1038/nrm2672

26. A. I. Walker, T. Hunt, R. J. Jackson and C. W. Anderson: Double-stranded DNA induces the phosphorylation of several proteins including the 90 000 mol. wt. heat-shock protein in animal cell extracts. EMBO Journal, 4(1), 139-145 (1985)
DOI: 10.1002/j.1460-2075.1985.tb02328.x

27. T. Mimori and J. A. Hardin: Mechanism of interaction between Ku protein and DNA. Journal of Biological Chemistry, 261(22), 10375-10379 (1986)

28. T. Carter, I. Vancurová, I. Sun, W. Lou and S. DeLeon: A DNA-activated protein kinase from HeLa cell nuclei. Molecular and Cellular Biology, 10(12), 6460 (1990)
DOI: 10.1128/MCB.10.12.6460

29. J. R. Walker, R. A. Corpina and J. Goldberg: Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature, 412(6847), 607-614 (2001)
DOI: 10.1038/35088000

30. D. Durocher and S. P. Jackson: DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol, 13(2), 225-31 (2001)
DOI: 10.1016/S0955-0674(00)00201-5

31. T. A. Dobbs, J. A. Tainer and S. P. Lees-Miller: A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation. DNA Repair (Amst), 9(12), 1307-14 (2010)
DOI: 10.1016/j.dnarep.2010.09.019

32. T. Stiff, M. O'Driscoll, N. Rief, K. Iwabuchi, M. Lobrich and P. A. Jeggo: ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res, 64(7), 2390-6 (2004)
DOI: 10.1158/0008-5472.CAN-03-3207

33. J. An, Y. C. Huang, Q. Z. Xu, L. J. Zhou, Z. F. Shang, B. Huang, Y. Wang, X. D. Liu, D. C. Wu and P. K. Zhou: DNA-PKcs plays a dominant role in the regulation of H2AX phosphorylation in response to DNA damage and cell cycle progression. BMC Mol Biol, 11, 18 (2010)
DOI: 10.1186/1471-2199-11-18

34. R. H. F. Wong, I. Chang, C. S. S. Hudak, S. Hyun, H.-Y. Kwan and H. S. Sul: A Role of DNA-PK for the Metabolic Gene Regulation in Response to Insulin. Cell, 136(6), 1056-1072 (2009)
DOI: 10.1016/j.cell.2008.12.040

35. W. D. Block, Y. Yu, D. Merkle, J. L. Gifford, Q. Ding, K. Meek and S. P. Lees-Miller: Autophosphorylation-dependent remodeling of the DNA-dependent protein kinase catalytic subunit regulates ligation of DNA ends. Nucleic Acids Res, 32(14), 4351-7 (2004)
DOI: 10.1093/nar/gkh761

36. E. Weterings, N. S. Verkaik, H. T. Bruggenwirth, J. H. Hoeijmakers and D. C. van Gent: The role of DNA dependent protein kinase in synapsis of DNA ends. Nucleic Acids Res, 31(24), 7238-46 (2003)
DOI: 10.1093/nar/gkg889

37. A. J. Davis, S. So and D. J. Chen: Dynamics of the PI3K-like protein kinase members ATM and DNA-PKcs at DNA double strand breaks. Cell Cycle, 9(13), 2529-36 (2010)
DOI: 10.4161/cc.9.13.12148

38. E. P. Morris, A. Rivera-Calzada, P. C. da Fonseca, O. Llorca, L. H. Pearl and L. Spagnolo: Evidence for a remodelling of DNA-PK upon autophosphorylation from electron microscopy studies. Nucleic Acids Res, 39(13), 5757-67 (2011)
DOI: 10.1093/nar/gkr146

39. J. M. Wagner and S. H. Kaufmann: Prospects for the Use of ATR Inhibitors to Treat Cancer. Pharmaceuticals, 3(5), 1311 (2010)
DOI: 10.3390/ph3051311

40. J. Yang, Z. P. Xu, Y. Huang, H. E. Hamrick, P. J. Duerksen-Hughes and Y. N. Yu: ATM and ATR: sensing DNA damage. World journal of gastroenterology : WJG, 10(2), 155-160 (2004)
DOI: 10.3748/wjg.v10.i2.155

41. J. D. Charrier, S. J. Durrant, J. M. Golec, D. P. Kay, R. M. Knegtel, S. MacCormick, M. Mortimore, M. E. O'Donnell, J. L. Pinder, P. M. Reaper, A. P. Rutherford, P. S. Wang, S. C. Young and J. R. Pollard: Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem, 54(7), 2320-30 (2011)
DOI: 10.1021/jm101488z

42. J. H. Lee and T. T. Paull: ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science, 308(5721), 551-4 (2005)
DOI: 10.1126/science.1108297

43. T. Uziel, Y. Lerenthal, L. Moyal, Y. Andegeko, L. Mittelman and Y. Shiloh: Requirement of the MRN complex for ATM activation by DNA damage. Embo j, 22(20), 5612-21 (2003)
DOI: 10.1093/emboj/cdg541

44. K. Savitsky, A. Bar-Shira, S. Gilad, G. Rotman, Y. Ziv, L. Vanagaite, D. A. Tagle, S. Smith, T. Uziel, S. Sfez, M. Ashkenazi, I. Pecker, M. Frydman, R. Harnik, S. R. Patanjali, A. Simmons, G. A. Clines, A. Sartiel, R. A. Gatti, L. Chessa, O. Sanal, M. F. Lavin, N. G. J. Jaspers, A. M. R. Taylor, C. F. Arlett, T. Miki, S. M. Weissman, M. Lovett, F. S. Collins and Y. Shiloh: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science, 268(5218), 1749-1753 (1995)
DOI: 10.1126/science.7792600

45. A. J. Lustig and T. D. Petes: Identification of yeast mutants with altered telomere structure. Proceedings of the National Academy of Sciences, 83(5), 1398 (1986)
DOI: 10.1073/pnas.83.5.1398

46. D. M. Morrow, D. A. Tagle, Y. Shiloh, F. S. Collins and P. Hieter: TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell, 82(5), 831-40 (1995)
DOI: 10.1016/0092-8674(95)90480-8

47. S. Burma, B. P. Chen, M. Murphy, A. Kurimasa and D. J. Chen: ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem, 276(45), 42462-7 (2001)
DOI: 10.1074/jbc.C100466200

48. R. S. Tibbetts, K. M. Brumbaugh, J. M. Williams, J. N. Sarkaria, W. A. Cliby, S. Y. Shieh, Y. Taya, C. Prives and R. T. Abraham: A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev, 13(2), 152-7 (1999)
DOI: 10.1101/gad.13.2.152

49. L. Zou and S. J. Elledge: Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes. Science, 300(5625), 1542-1548 (2003)
DOI: 10.1126/science.1083430

50. V. Ellison and B. Stillman: Biochemical Characterization of DNA Damage Checkpoint Complexes: Clamp Loader and Clamp Complexes with Specificity for 5′ Recessed DNA. PLOS Biology, 1(2), e33 (2003)
DOI: 10.1371/journal.pbio.0000033

51. A. Kumagai, J. Lee, H. Y. Yoo and W. G. Dunphy: TopBP1 Activates the ATR-ATRIP Complex. Cell, 124(5), 943-955 (2006)
DOI: 10.1016/j.cell.2005.12.041

52. H. Y. Yoo, A. Shevchenko, A. Shevchenko and W. G. Dunphy: Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses. J Biol Chem, 279(51), 53353-64 (2004)
DOI: 10.1074/jbc.M408026200

53. J. S. Liu, S. R. Kuo and T. Melendy: Phosphorylation of replication protein A by S-phase checkpoint kinases. DNA Repair (Amst), 5(3), 369-80 (2006)
DOI: 10.1016/j.dnarep.2005.11.007

54. J. Chen: Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage. Cancer Res, 60(18), 5037-9 (2000)

55. K. M. Brumbaugh, D. M. Otterness, C. Geisen, V. Oliveira, J. Brognard, X. Li, F. Lejeune, R. S. Tibbetts, L. E. Maquat and R. T. Abraham: The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells. Mol Cell, 14(5), 585-98 (2004)
DOI: 10.1016/j.molcel.2004.05.005

56. A. Yamashita, N. Izumi, I. Kashima, T. Ohnishi, B. Saari, Y. Katsuhata, R. Muramatsu, T. Morita, A. Iwamatsu, T. Hachiya, R. Kurata, H. Hirano, P. Anderson and S. Ohno: SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay. Genes & development, 23(9), 1091-1105 (2009)
DOI: 10.1101/gad.1767209

57. R. Melero, A. Uchiyama, R. Castano, N. Kataoka, H. Kurosawa, S. Ohno, A. Yamashita and O. Llorca: Structures of SMG1-UPFs complexes: SMG1 contributes to regulate UPF2-dependent activation of UPF1 in NMD. Structure, 22(8), 1105-1119 (2014)
DOI: 10.1016/j.str.2014.05.015

58. P. V. Ivanov, N. H. Gehring, J. B. Kunz, M. W. Hentze and A. E. Kulozik: Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. Embo j, 27(5), 736-47 (2008)
DOI: 10.1038/emboj.2008.17

59. I. Melnikova and J. Golden: Targeting protein kinases. Nature Reviews Drug Discovery, 3(12), 993-994 (2004)
DOI: 10.1038/nrd1600

60. Daniel K. Treiber and Neil P. Shah: Ins and Outs of Kinase DFG Motifs. Chemistry & Biology, 20(6), 745-746 (2013)
DOI: 10.1016/j.chembiol.2013.06.001

61. Y. H. Peng, H. Y. Shiao, C. H. Tu, P. M. Liu, J. T. Hsu, P. K. Amancha, J. S. Wu, M. S. Coumar, C. H. Chen, S. Y. Wang, W. H. Lin, H. Y. Sun, Y. S. Chao, P. C. Lyu, H. P. Hsieh and S. Y. Wu: Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. J Med Chem, 56(10), 3889-903 (2013)
DOI: 10.1021/jm400072p

62. F. Zuccotto, E. Ardini, E. Casale and M. Angiolini: Through the "Gatekeeper Door": Exploiting the Active Kinase Conformation. Journal of Medicinal Chemistry, 53(7), 2681-2694 (2010)
DOI: 10.1021/jm901443h

63. J. N. Sarkaria, R. S. Tibbetts, E. C. Busby, A. P. Kennedy, D. E. Hill and R. T. Abraham: Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res, 58(19), 4375-82 (1998)

64. B. D. Price and M. B. Youmell: The phosphatidylinositol 3-kinase inhibitor wortmannin sensitizes murine fibroblasts and human tumor cells to radiation and blocks induction of p53 following DNA damage. Cancer Res, 56(2), 246-50 (1996)

65. S.-L. Yao, A. J. Akhtar, K. A. McKenna, G. C. Bedi, D. Sidransky, M. Mabry, R. Ravi, M. I. Collector, R. J. Jones, S. J. Sharkis, E. J. Fuchs and A. Bedi: Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34cdc2 kinase. Nature Medicine, 2(10), 1140-1143 (1996)
DOI: 10.1038/nm1096-1140

66. A. Blasina, B. D. Price, G. A. Turenne and C. H. McGowan: Caffeine inhibits the checkpoint kinase ATM. Current Biology, 9(19), 1135-1138 (1999)
DOI: 10.1016/S0960-9822(99)80486-2

67. H. Nishida, N. Tatewaki, Y. Nakajima, T. Magara, K. M. Ko, Y. Hamamori and T. Konishi: Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Res, 37(17), 5678-89 (2009)
DOI: 10.1093/nar/gkp593

68. N. Tatewaki, H. Nishida, M. Yoshida, H. Ando, S. Kondo, T. Sakamaki and T. Konishi: Differential effect of schisandrin B stereoisomers on ATR-mediated DNA damage checkpoint signaling. J Pharmacol Sci, 122(2), 138-48 (2013)
DOI: 10.1254/jphs.13048FP

69. J. Li, S. G. Kim and J. Blenis: Rapamycin: one drug, many effects. Cell metabolism, 19(3), 373-379 (2014)
DOI: 10.1016/j.cmet.2014.01.001

70. A. Y. Choo, S. O. Yoon, S. G. Kim, P. P. Roux and J. Blenis: Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci U S A, 105(45), 17414-9 (2008)
DOI: 10.1073/pnas.0809136105

71. C. H. Aylett, E. Sauer, S. Imseng, D. Boehringer, M. N. Hall, N. Ban and T. Maier: Architecture of human mTOR complex 1. Science, 351(6268), 48-52 (2016)
DOI: 10.1126/science.aaa3870

72. B. Geoerger, K. Kerr, C. B. Tang, K. M. Fung, B. Powell, L. N. Sutton, P. C. Phillips and A. J. Janss: Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res, 61(4), 1527-32 (2001)

73. W. Schuler, R. Sedrani, S. Cottens, B. Haberlin, M. Schulz, H. J. Schuurman, G. Zenke, H. G. Zerwes and M. H. Schreier: SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation, 64(1), 36-42 (1997)
DOI: 10.1097/00007890-199707150-00008

74. C. J. Vlahos, W. F. Matter, K. Y. Hui and R. F. Brown: A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem, 269(7), 5241-8 (1994)

75. R. A. Izzard, S. P. Jackson and G. C. Smith: Competitive and noncompetitive inhibition of the DNA-dependent protein kinase. Cancer Res, 59(11), 2581-6 (1999)

76. R. J. Griffin, G. Fontana, B. T. Golding, S. Guiard, I. R. Hardcastle, J. J. J. Leahy, N. Martin, C. Richardson, L. Rigoreau, M. Stockley and G. C. M. Smith: Selective Benzopyranone and Pyrimido[2,1-a]isoquinolin-4-one Inhibitors of DNA-Dependent Protein Kinase:  Synthesis, Structure−Activity Studies, and Radiosensitization of a Human Tumor Cell Line in Vitro. Journal of Medicinal Chemistry, 48(2), 569-585 (2005)
DOI: 10.1021/jm049526a

77. J. J. Hollick, B. T. Golding, I. R. Hardcastle, N. Martin, C. Richardson, L. J. M. Rigoreau, G. C. M. Smith and R. J. Griffin: 2,6-Disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK). Bioorganic & Medicinal Chemistry Letters, 13(18), 3083-3086 (2003)
DOI: 10.1016/S0960-894X(03)00652-8

78. I. Hickson, Y. Zhao, C. J. Richardson, S. J. Green, N. M. B. Martin, A. I. Orr, P. M. Reaper, S. P. Jackson, N. J. Curtin and G. C. M. Smith: Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM. Cancer Research, 64(24), 9152-9159 (2004) doi:10.1158/0008-5472.can-04-2727
DOI: 10.1158/0008-5472.CAN-04-2727

79. Y. Li and D. Q. Yang: The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther, 9(1), 113-25 (2010)
DOI: 10.1158/1535-7163.MCT-08-1189

80. S. E. Golding, E. Rosenberg, B. R. Adams, S. Wignarajah, J. M. Beckta, M. J. O'Connor and K. Valerie: Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Cell Cycle, 11(6), 1167-1173 (2012)
DOI: 10.4161/cc.11.6.19576

81. Q. Liu, J. W. Chang, J. Wang, S. A. Kang, C. C. Thoreen, A. Markhard, W. Hur, J. Zhang, T. Sim, D. M. Sabatini and N. S. Gray: Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benz o[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J Med Chem, 53(19), 7146-55 (2010)
DOI: 10.1021/jm101144f

82. Q. Liu, C. Xu, S. Kirubakaran, X. Zhang, W. Hur, Y. Liu, N. P. Kwiatkowski, J. Wang, K. D. Westover, P. Gao, D. Ercan, M. Niepel, C. C. Thoreen, S. A. Kang, M. P. Patricelli, Y. Wang, T. Tupper, A. Altabef, H. Kawamura, K. D. Held, D. M. Chou, S. J. Elledge, P. A. Janne, K. K. Wong, D. M. Sabatini and N. S. Gray: Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer Res, 73(8), 2574-86 (2013)
DOI: 10.1158/0008-5472.CAN-12-1702

83. Q. Liu, J. Wang, S. A. Kang, C. C. Thoreen, W. Hur, T. Ahmed, D. M. Sabatini and N. S. Gray: Discovery of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a Potent, Selective, and Orally Available Mammalian Target of Rapamycin (mTOR) Inhibitor for Treatment of Cancer. Journal of Medicinal Chemistry, 54(5), 1473-1480 (2011)
DOI: 10.1021/jm101520v

84. A. Shaik, R. Bhakuni and S. Kirubakaran: Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors. Molecules, 23(5), 992 (2018)
DOI: 10.3390/molecules23050992

85. S.-M. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell, C. Fritsch, S. Brachmann, P. Chène, A. De Pover, K. Schoemaker, D. Fabbro, D. Gabriel, M. Simonen, L. Murphy, P. Finan, W. Sellers and C. García-Echeverría: Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Molecular Cancer Therapeutics, 7(7), 1851 (2008)
DOI: 10.1158/1535-7163.MCT-08-0017

86. L. I. Toledo, M. Murga, R. Zur, R. Soria, A. Rodriguez, S. Martinez, J. Oyarzabal, J. Pastor, J. R. Bischoff and O. Fernandez-Capetillo: A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nature Structural &Amp; Molecular Biology, 18, 721 (2011) 87. L. I. Toledo, M. Murga and O. Fernandez-Capetillo: Targeting ATR and Chk1 kinases for cancer treatment: a new model for new (and old) drugs. Mol Oncol, 5(4), 368-73 (2011)
DOI: 10.1016/j.molonc.2011.07.002

88. S. T. Durant, L. Zheng, Y. Wang, K. Chen, L. Zhang, T. Zhang, Z. Yang, L. Riches, A. G. Trinidad, J. H. L. Fok, T. Hunt, K. G. Pike, J. Wilson, A. Smith, N. Colclough, V. P. Reddy, A. Sykes, A. Janefeldt, P. Johnström, K. Varnäs, A. Takano, S. Ling, J. Orme, J. Stott, C. Roberts, I. Barrett, G. Jones, M. Roudier, A. Pierce, J. Allen, J. Kahn, A. Sule, J. Karlin, A. Cronin, M. Chapman, K. Valerie, R. Illingworth and M. Pass: The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Science Advances, 4(6), eaat1719 (2018)
DOI: 10.1126/sciadv.aat1719

89. S. L. Degorce, B. Barlaam, E. Cadogan, A. Dishington, R. Ducray, S. C. Glossop, L. A. Hassall, F. Lach, A. Lau, T. M. McGuire, T. Nowak, G. Ouvry, K. G. Pike and A. G. Thomason: Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase. J Med Chem, 59(13), 6281-92 (2016)
DOI: 10.1021/acs.jmedchem.6b00519

90. B. Barlaam, E. Cadogan, A. Campbell, N. Colclough, A. Dishington, S. Durant, K. Goldberg, L. A. Hassall, G. D. Hughes, P. A. MacFaul, T. M. McGuire, M. Pass, A. Patel, S. Pearson, J. Petersen, K. G. Pike, G. Robb, N. Stratton, G. Xin and B. Zhai: Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors. ACS Medicinal Chemistry Letters, 9(8), 809-814 (2018)
DOI: 10.1021/acsmedchemlett.8b00200

91. R. Prevo, E. Fokas, P. M. Reaper, P. A. Charlton, J. R. Pollard, W. G. McKenna, R. J. Muschel and T. B. Brunner: The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer biology & therapy, 13(11), 1072-1081 (2012)
DOI: 10.4161/cbt.21093

92. I. M. Pires, M. M. Olcina, S. Anbalagan, J. R. Pollard, P. M. Reaper, P. A. Charlton, W. G. McKenna and E. M. Hammond: Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. British Journal Of Cancer, 107, 291 (2012)
DOI: 10.1038/bjc.2012.265

93. Q. Rao, M. Liu, Y. Tian, Z. Wu, Y. Hao, L. Song, Z. Qin, C. Ding, H.-W. Wang, J. Wang and Y. Xu: Cryo-EM structure of human ATR-ATRIP complex. Cell Research, 28, 143 (2017)
DOI: 10.1038/cr.2017.158

94. A. B. Hall, D. Newsome, Y. Wang, D. M. Boucher, B. Eustace, Y. Gu, B. Hare, M. A. Johnson, S. Milton, C. E. Murphy, D. Takemoto, C. Tolman, M. Wood, P. Charlton, J. D. Charrier, B. Furey, J. Golec, P. M. Reaper and J. R. Pollard: Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget, 5(14), 5674-85 (2014)
DOI: 10.18632/oncotarget.2158

95. B. O'Carrigan, M. J. de Miguel Luken, D. Papadatos-Pastos, J. Brown, N. Tunariu, R. Perez Lopez, M. Ganegoda, R. Riisnaes, I. Figueiredo, S. Carreira, B. Hare, F. Yang, K. McDermott, M. S. Penney, J. Pollard, J. S. Lopez, U. Banerji, J. S. De Bono, S. Z. Fields and T. A. Yap: Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies. Journal of Clinical Oncology, 34(15_suppl), 2504-2504 (2016)
DOI: 10.1200/JCO.2016.34.15_suppl.2504

96. A. Peasland, L. Z. Wang, E. Rowling, S. Kyle, T. Chen, A. Hopkins, W. A. Cliby, J. Sarkaria, G. Beale, R. J. Edmondson and N. J. Curtin: Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. British Journal Of Cancer, 105, 372 (2011)
DOI: 10.1038/bjc.2011.243

97. A. Gopalsamy, E. M. Bennett, M. Shi, W.-G. Zhang, J. Bard and K. Yu: Identification of pyrimidine derivatives as hSMG-1 inhibitors. Bioorganic & Medicinal Chemistry Letters, 22(21), 6636-6641 (2012)
DOI: 10.1016/j.bmcl.2012.08.107

98. S. Llona-Minguez, A. Hoglund, S. A. Jacques, T. Koolmeister and T. Helleday: Chemical strategies for development of ATR inhibitors. Expert Rev Mol Med, 9(16), 10 (2014)
DOI: 10.1017/erm.2014.10

99. K. M. Foote and J. W. M. Nissink: Pyrimidine indole derivatives for treating cancer. In: Google Patents, (2010)

100. R. Jossé, S. E. Martin, R. Guha, P. Ormanoglu, T. D. Pfister, P. M. Reaper, C. S. Barnes, J. Jones, P. Charlton, J. R. Pollard, J. Morris, J. H. Doroshow and Y. Pommier: ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer research, 74(23), 6968-6979 (2014)
DOI: 10.1158/0008-5472.CAN-13-3369

101. J.-D. Charrier, S. J. Durrant, J. M. C. Golec, D. P. Kay, R. M. A. Knegtel, S. MacCormick, M. Mortimore, M. E. O'Donnell, J. L. Pinder, P. M. Reaper, A. P. Rutherford, P. S. H. Wang, S. C. Young and J. R. Pollard: Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents. Journal of Medicinal Chemistry, 54(7), 2320-2330 (2011)
DOI: 10.1021/jm101488z

102. P. M. Reaper, M. R. Griffiths, J. M. Long, J. D. Charrier, S. Maccormick, P. A. Charlton, J. M. Golec and J. R. Pollard: Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol, 7(7), 428-30 (2011)
DOI: 10.1038/nchembio.573

103. C. T. Williamson, R. Miller, H. N. Pemberton, S. E. Jones, J. Campbell, A. Konde, N. Badham, R. Rafiq, R. Brough, A. Gulati, C. J. Ryan, J. Francis, P. B. Vermulen, A. R. Reynolds, P. M. Reaper, J. R. Pollard, A. Ashworth and C. J. Lord: ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nature Communications, 7, 13837 (2016)
DOI: 10.1038/ncomms13837

104. E. Fokas, R. Prevo, J. R. Pollard, P. M. Reaper, P. A. Charlton, B. Cornelissen, K. A. Vallis, E. M. Hammond, M. M. Olcina, W. Gillies McKenna, R. J. Muschel and T. B. Brunner: Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death & Disease, 3(12), e441-e441 (2012)
DOI: 10.1038/cddis.2012.181

105. A. Thomas, C. E. Redon, L. Sciuto, E. Padiernos, J. Ji, M. J. Lee, A. Yuno, S. Lee, Y. Zhang, L. Tran, W. Yutzy, A. Rajan, U. Guha, H. Chen, R. Hassan, C. C. Alewine, E. Szabo, S. E. Bates, R. J. Kinders, S. M. Steinberg, J. H. Doroshow, M. I. Aladjem, J. B. Trepel and Y. Pommier: Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol, 36(16), 1594-1602 (2018)
DOI: 10.1200/JCO.2017.76.6915

106. K. M. Foote, K. Blades, A. Cronin, S. Fillery, S. S. Guichard, L. Hassall, I. Hickson, X. Jacq, P. J. Jewsbury, T. M. McGuire, J. W. M. Nissink, R. Odedra, K. Page, P. Perkins, A. Suleman, K. Tam, P. Thommes, R. Broadhurst and C. Wood: Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity. Journal of Medicinal Chemistry, 56(5), 2125-2138 (2013)
DOI: 10.1021/jm301859s

107. F. P. Vendetti, A. Lau, S. Schamus, T. P. Conrads, M. J. O'Connor and C. J. Bakkenist: The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget, 6(42), 44289-305 (2015)
DOI: 10.18632/oncotarget.6247

108. M. T. Dillon, Z. Boylan, D. Smith, J. Guevara, K. Mohammed, C. Peckitt, M. Saunders, U. Banerji, G. Clack, S. A. Smith, J. F. Spicer, M. D. Forster and K. J. Harrington: PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours. Clin Transl Radiat Oncol, 12, 16-20 (2018)
DOI: 10.1016/j.ctro.2018.06.001

109. L. I. Toledo, M. Murga, R. Zur, R. Soria, A. Rodriguez, S. Martinez, J. Oyarzabal, J. Pastor, J. R. Bischoff and O. Fernandez-Capetillo: A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol, 18(6), 721-7 (2011)
DOI: 10.1038/nsmb.2076

110. F. P. Vendetti, B. J. Leibowitz, J. Barnes, S. Schamus, B. F. Kiesel, S. Abberbock, T. Conrads, D. A. Clump, E. Cadogan, M. J. O'Connor, J. Yu, J. H. Beumer and C. J. Bakkenist: Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation. Scientific Reports, 7, 41892 (2017)
DOI: 10.1038/srep41892

111. G. Hudes, M. Carducci, P. Tomczak, J. Dutcher, R. Figlin, A. Kapoor, E. Staroslawska, J. Sosman, D. McDermott, I. Bodrogi, Z. Kovacevic, V. Lesovoy, I. G. Schmidt-Wolf, O. Barbarash, E. Gokmen, T. O'Toole, S. Lustgarten, L. Moore and R. J. Motzer: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med, 356(22), 2271-81 (2007)
DOI: 10.1056/NEJMoa066838

112. M. Hidalgo, J. C. Buckner, C. Erlichman, M. S. Pollack, J. P. Boni, G. Dukart, B. Marshall, L. Speicher, L. Moore and E. K. Rowinsky: A Phase I and Pharmacokinetic Study of Temsirolimus (CCI-779) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients with Advanced Cancer. Clinical Cancer Research, 12(19), 5755 (2006)
DOI: 10.1158/1078-0432.CCR-06-0118

113. R. J. Amato, J. Jac, S. Giessinger, S. Saxena and J. P. Willis: A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer, 115(11), 2438-46 (2009)
DOI: 10.1002/cncr.24280

114. R. J. Motzer, B. Escudier, S. Oudard, T. E. Hutson, C. Porta, S. Bracarda, V. Grunwald, J. A. Thompson, R. A. Figlin, N. Hollaender, G. Urbanowitz, W. J. Berg, A. Kay, D. Lebwohl and A. Ravaud: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet, 372(9637), 449-56 (2008)
DOI: 10.1016/S0140-6736(08)61039-9

115. S. H. Ou, J. Moon, L. L. Garland, P. C. Mack, J. R. Testa, A. S. Tsao, A. J. Wozniak and D. R. Gandara: SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). J Thorac Oncol, 10(2), 387-91 (2015)
DOI: 10.1097/JTO.0000000000000360

116. A. Naing, C. Aghajanian, E. Raymond, D. Olmos, G. Schwartz, E. Oelmann, L. Grinsted, W. Burke, R. Taylor, S. Kaye, R. Kurzrock and U. Banerji: Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer, 107(7), 1093-9 (2012)
DOI: 10.1038/bjc.2012.368

117. K. G. Pike, K. Malagu, M. G. Hummersone, K. A. Menear, H. M. Duggan, S. Gomez, N. M. Martin, L. Ruston, S. L. Pass and M. Pass: Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett, 23(5), 1212-6 (2013)
DOI: 10.1016/j.bmcl.2013.01.019

118. U. Banerji, C. Aghajanian, E. Raymond, R. Kurzrock, M. Blanco-Codesido, E. Oelmann, L. Grinsted, W. Burke, S. B. Kaye and A. Naing: First results from a phase I trial of AZD8055, a dual mTORC1 and mTORC2 inhibitor. Journal of Clinical Oncology, 29(15_suppl), 3096-3096 (2011)
DOI: 10.1200/jco.2011.29.15_suppl.3096

119. N. Carayol, E. Vakana, A. Sassano, S. Kaur, D. J. Goussetis, H. Glaser, B. J. Druker, N. J. Donato, J. K. Altman, S. Barr and L. C. Platanias: Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci U S A, 107(28), 12469-74 (2010)
DOI: 10.1073/pnas.1005114107

120. J. Mateo, D. Olmos, H. Dumez, S. Poondru, N. L. Samberg, S. Barr, J. M. Van Tornout, F. Jie, S. Sandhu, D. S. Tan, V. Moreno, P. M. LoRusso, S. B. Kaye and P. Schöffski: A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies. British Journal of Cancer, 114(8), 889-896 (2016)
DOI: 10.1038/bjc.2016.59

121. C. Garcia-Garcia, Y. H. Ibrahim, V. Serra, M. T. Calvo, M. Guzman, J. Grueso, C. Aura, J. Perez, K. Jessen, Y. Liu, C. Rommel, J. Tabernero, J. Baselga and M. Scaltriti: Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res, 18(9), 2603-12 (2012)
DOI: 10.1158/1078-0432.CCR-11-2750

122. C. Li, J. F. Cui, M. B. Chen, C. Y. Liu, F. Liu, Q. D. Zhang, J. Zou and P. H. Lu: The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent. Cancer Biol Ther, 16(1), 34-42 (2015)
DOI: 10.4161/15384047.2014.972274

Abbreviations: PIKKs: Phosphatidylinositol-3 kinase-related kinases, PI3K: Phosphatidylinositol 3-kinase, ATM: Ataxia telangiectasia mutated kinase, ATR: ATM- and Rad3-related kinase, DNA-PKcs: DNA dependent protein kinase catalytic subunit, mTOR: mammalian target of rapamycin, SMG: suppressor with morphological effect on genitalia family member, TRAAP: Transformation/transcription-associated protein, FAT domain: FRAP, ATM, and TRRAP, FRB: FKBP- rapamycin binding, ATRIP: ATR-interacting protein, TopBP1: Topoisomerase binding protein I, 4EBP1: eIF4E-binding protein 1, S6K1: ribosomal S6 kinases, PKCα: Protein Kinase C α, HM: hydrophobic motif, DSBs; DNA doble strand breaks, SSBs: DNA single strand breaks, RPA: replication-associated protein A, DDR: DNA damage and response, MRN: Mre11-Rad50-Nbs1, Chk1: checkpoint kinase 1, Chk2: checkpoint kinase 2, UV: Ultraviolet, IR: Ionizing radiation, BRCA1: breast cancer suppressor protein 1, NMD: nonsense-mediated mRNA decay, KD: Kinase domain, ATP: Adenosine triphosphate, SchB: Schisandrin B, PARP: poly (ADP-ribose) polymerase, CDK1: Cyclin dependent kinase 1.

Key Words: Carcinoma, cancer, inhibitors, protein kinases, kinase domain, catalytic activity, Phosphatidylinositol-3 kinase-related kinases, Phosphatidylinositol 3-kinase, Ataxia telangiectasia mutated kinase, ATM- and Rad3-related kinase, DNA dependent protein kinase catalytic subunit, mammalian target of rapamycin (mTOR), SMG: suppressor with morphological effect on genitalia family member (SMG), Transformation/transcription-associated protein (TRAAP), quinolines, clinical trials, pharmacodynamics, pharmacokinetics, IC50, solubility, bioavailability, thiaanthrenpyran-4-one, Rapalogs, pyrazine derivatives, pyrimidine derivatives, schisandrin, caffeine, wortmannin, Auto phosphorylation, DFG motif

Send correspondence to: Sivapriya Kirubakaran, Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India, 382355, Tel: 91-9925906242, E-mail: priyak@iitgn.ac.in