Advertisement

Clinical Development of CHK1 Inhibitors

  • Alvaro Ingles Garces
  • Udai Banerji
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Checkpoint kinase 1 (CHK1) is an intracellular multifunctional serine/threonine kinase and an important component in the regulation of the DNA damage response (DDR) (Dai and Grant 2010; Hong et al. 2016). Broadly, its function is to maintain the integrity of cellular DNA from intrinsic or genotoxic agent-induced DNA damage i.e. single- or double-strand breaks and stalled replication forks by interrupting progression of a cell through the cell cycle. The validation of CHK1 as a target in cancer therapeutics has been discussed in previous chapters.

Keywords

Checkpoint CHK1 inhibitors CHK1 clinical trials Biomarkers AZD7762 GDC-0425 LY2606368 MK-8776 PF-736 SRA737 

References

  1. Barker HE, Patel R, McLaughlin M, Schick U, Zaidi S, Nutting CM, Newbold KL, Bhide S, Harrington KJ (2016) CHK1 inhibition radiosensitizes head and neck cancers to paclitaxel-based chemoradiotherapy. Mol Cancer Ther 15:2042–2054CrossRefPubMedGoogle Scholar
  2. Benada J, Macurek L (2015) Targeting the checkpoint to kill cancer cells. Biomol Ther 5:1912–1937Google Scholar
  3. Borst GR, McLaughlin M, Kyula JN, Neijenhuis S, Khan A, Good J, Zaidi S, Powell NG, Meier P, Collins I et al (2013) Targeted radiosensitization by the Chk1 inhibitor SAR-020106. Int J Radiat Oncol Biol Phys 85:1110–1118CrossRefPubMedGoogle Scholar
  4. Brega N, McArthur GA, Britten C, Wong SG, Wang E, Wilner KD, Blasina A, Schwartz GK, Gallo J, Tse AN (2010) Phase I clinical trial of gemcitabine (GEM) in combination with PF-00477736 (PF-736), a selective inhibitor of CHK1 kinase. In: ASCO annual meeting. Chicago, USA. J Clin Oncol 28:15sCrossRefGoogle Scholar
  5. Bridges KA, Chen X, Liu H, Rock C, Buchholz TA, Shumway SD, Skinner HD, Meyn RE (2016) MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Oncotarget 7(44):71660–71672CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bryant C, Scriven K, Massey AJ (2014) Inhibition of the checkpoint kinase Chk1 induces DNA damage and cell death in human leukemia and lymphoma cells. Mol Cancer 13:147CrossRefPubMedPubMedCentralGoogle Scholar
  7. Calvo E, Chen VJ, Marshall M, Ohnmacht U, Hynes SM, Kumm E, Diaz HB, Barnard D, Merzoug FF, Huber L et al (2014) Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer. Investig New Drugs 32:955–968CrossRefGoogle Scholar
  8. Cancer Genome Atlas Research N (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615CrossRefGoogle Scholar
  9. Chaudhuri L, Vincelette ND, Koh BD, Naylor RM, Flatten KS, Peterson KL, McNally A, Gojo I, Karp JE, Mesa RA et al (2014) CHK1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo. Haematologica 99:688–696CrossRefPubMedPubMedCentralGoogle Scholar
  10. ClincalTrials.Gov (2016a) ClincalTrials.Gov: a CRUK phase I trial of CCT245737 in patients with advanced cancer. https://clinicaltrials.gov/ct2/results?term=NCT02797964&Search=Search
  11. ClincalTrials.Gov (2016b) ClinicalTrials.Gov: a CRUK phase I trial of CCT245737 in combination with gemcitabine plus cisplatin or gemcitabine alone in patients with advanced cancer. https://clinicaltrials.gov/ct2/results?term=NCT02797977&Search=Search
  12. ClinicalTrials.Gov (2018) A study of GDC-0575 alone and in combination with gemcitabine in patients with refractory solid tumors or lymphoma. https://clinicaltrials.gov/ct2/show/NCT01564251?term=GDC-0575&rank=1:
  13. Cole KA, Huggins J, Laquaglia M, Hulderman CE, Russell MR, Bosse K, Diskin SJ, Attiyeh EF, Sennett R, Norris G et al (2011) RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma. Proc Natl Acad Sci U S A 108:3336–3341CrossRefPubMedPubMedCentralGoogle Scholar
  14. Dai Y, Grant S (2010) New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res 16:376–383CrossRefPubMedPubMedCentralGoogle Scholar
  15. Daud AI, Ashworth MT, Strosberg J, Goldman JW, Mendelson D, Springett G, Venook AP, Loechner S, Rosen LS, Shanahan F et al (2015) Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J Clin Oncol 33:1060–1066CrossRefPubMedGoogle Scholar
  16. Doi T, Yoshino T, Shitara K, Matsubara N, Fuse N, Naito Y, Uenaka K, Nakamura T, Hynes SM, Lin AB (2015) Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors. Anti-Cancer Drugs 26:1043–1053CrossRefPubMedGoogle Scholar
  17. Garrett MD, Collins I (2011) Anticancer therapy with checkpoint inhibitors: what, where and when? Trends Pharmacol Sci 32:308–316CrossRefPubMedGoogle Scholar
  18. Guertin AD, Martin MM, Roberts B, Hurd M, Qu X, Miselis NR, Liu Y, Li J, Feldman I, Benita Y et al (2012) Unique functions of CHK1 and WEE1 underlie synergistic anti-tumor activity upon pharmacologic inhibition. Cancer Cell Int 12:45CrossRefPubMedPubMedCentralGoogle Scholar
  19. Guzi TJ, Paruch K, Dwyer MP, Labroli M, Shanahan F, Davis N, Taricani L, Wiswell D, Seghezzi W, Penaflor E et al (2011) Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther 10:591–602CrossRefPubMedGoogle Scholar
  20. Ho AL, Bendell JC, Cleary JM, Schwartz GK, Burris HA, Oakes P, Agbo F, Barker PN, Senderowicz AM, Shapiro G (2011) Phase I, open-label, dose-escalation study of AZD7762 in combination with irinotecan (irino) in patients (pts) with advanced solid tumors. In: ASCO annual meeting, Chicago. J Clin Oncol 29(Suppl):3033–3033CrossRefGoogle Scholar
  21. Hong D, Infante J, Janku F, Jones S, Nguyen LM, Burris H, Naing A, Bauer TM, Piha-Paul S, Johnson FM et al (2016) Phase I study of LY2606368, a checkpoint kinase 1 inhibitor, in patients with advanced cancer. J Clin Oncol 34:1764–1771CrossRefPubMedPubMedCentralGoogle Scholar
  22. Infante JR, Hollebecque A, Postel-Vinay S, Bauer T, Blackwood B, Evangelista M, Mahrus S, Peale F, Lu X, Sahasranaman S et al (2015) Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors. In: Proceedings of the 106th annual AACR meeting,18–22 Apr 2015, Philadelphia, PA, USA. Cancer Res 75(15 Suppl):abstract nr CT139CrossRefGoogle Scholar
  23. Janetka JW, Ashwell S, Zabludoff S, Lyne P (2007) Inhibitors of checkpoint kinases: from discovery to the clinic. Curr Opin Drug Discov Devel 10:473–486PubMedGoogle Scholar
  24. Karnitz LM, Flatten KS, Wagner JM, Loegering D, Hackbarth JS, Arlander SJ, Vroman BT, Thomas MB, Baek YU, Hopkins KM et al (2005) Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. Mol Pharmacol 68:1636–1644PubMedGoogle Scholar
  25. Karp JE, Thomas BM, Greer JM, Sorge C, Gore SD, Pratz KW, Smith BD, Flatten KS, Peterson K, Schneider P et al (2012) Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias. Clin Cancer Res 18:6723–6731CrossRefPubMedPubMedCentralGoogle Scholar
  26. Karzai F, Zimmer A, Lipkowitz S, Annunziata CM, Parker B, Houston N, Ekwede I, Kohn EC, Lee J-M (2016) A phase II study of the cell cycle checkpoint kinases 1 and 2 (CHK1/2) inhibitor (LY2606368); prexasertib in sporadic triple negative breast cancer (TNBC). In: ESMO congress, Copenhagen, Denmark. Ann Oncol 27(Suppl 6):296–312Google Scholar
  27. Kim MK, James J, Annunziata CM (2015) Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells. BMC Cancer 15:196CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kobayashi H, Shigetomi H, Yoshimoto C (2015) Checkpoint kinase 1 inhibitors as targeted molecular agents for clear cell carcinoma of the ovary. Oncol Lett 10:571–576CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kulkarni A, Natarajan SK, Chandrasekar V, Pandey PR, Sengupta S (2016) Combining immune checkpoint inhibitors and kinase-inhibiting supramolecular therapeutics for enhanced anticancer efficacy. ACS Nano 10(10): 9227–9242CrossRefGoogle Scholar
  30. Laquente B, Lopez-Martin J, Richards D, Illerhaus G, Chang DZ, Kim G, Stella P, Richel D, Szcylik C, Cascinu S et al (2017) A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients. BMC Cancer 17:137CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lee J-M, Karzai FH, Zimmer A, Annunziata CM, Lipkowitz S, Parker B, Houston N, Ekwede I, Kohn EC (2016) A phase II study of the cell cycle checkpoint kinases 1 and 2 inhibitor (LY2606368; Prexasertib monomestylate monohydrate) in sporadic high-grade serous ovarian cancer (gBRCAm+ OvCa). In: ESMO congress 2016. Copenhagen, Denmark. Ann Oncol 27(Suppl 6):296–312Google Scholar
  32. Leijen S, Schellens JH, Shapiro G, Pavlick AC, Tibes R, Demuth T, Viscusi J, Cheng JD, Xu Y, Oza AM (2010) A phase I pharmacological and pharmacodynamic study of MK-1775, a Weel tyrosine kinase inhibitor, in monotherapy and combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J Clin Oncol 28:3067–3067CrossRefGoogle Scholar
  33. Lu HR, Wang X, Wang Y (2006) A stronger DNA damage-induced G2 checkpoint due to over-activated CHK1 in the absence of PARP-1. Cell Cycle 5:2364–2370CrossRefPubMedGoogle Scholar
  34. Ma CX, Janetka JW, Piwnica-Worms H (2011) Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol Med 17:88–96CrossRefPubMedGoogle Scholar
  35. Montano R, Chung I, Garner KM, Parry D, Eastman A (2012) Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites. Mol Cancer Ther 11:427–438CrossRefPubMedGoogle Scholar
  36. Morgan MA, Parsels LA, Maybaum J, Lawrence TS (2008) Improving gemcitabine-mediated radiosensitization using molecularly targeted therapy: a review. Clin Cancer Res 14:6744–6750CrossRefPubMedPubMedCentralGoogle Scholar
  37. Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, Colombo N, Spacek J, Vuylsteke P, Hirte H et al (2015) Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol 16:87–97CrossRefPubMedGoogle Scholar
  38. Sanjiv K, Hagenkort A, Calderon-Montano JM, Koolmeister T, Reaper PM, Mortusewicz O, Jacques SA, Kuiper RV, Schultz N, Scobie M et al (2016) Cancer-specific synthetic lethality between ATR and CHK1 kinase activities. Cell Rep 14:298–309CrossRefPubMedGoogle Scholar
  39. Sausville E, Lorusso P, Carducci M, Carter J, Quinn MF, Malburg L, Azad N, Cosgrove D, Knight R, Barker P et al (2014) Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors. Cancer Chemother Pharmacol 73:539–549CrossRefPubMedPubMedCentralGoogle Scholar
  40. Scagliotti G, Kang JH, Smith D, Rosenberg R, Park K, Kim SW, Su WC, Boyd TE, Richards DA, Novello S et al (2016) Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer. Investig New Drugs 34:625–635CrossRefGoogle Scholar
  41. Seto T, Esaki T, Hirai F, Arita S, Nosaki K, Makiyama A, Kometani T, Fujimoto C, Hamatake M, Takeoka H et al (2013) Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours. Cancer Chemother Pharmacol 72:619–627CrossRefPubMedGoogle Scholar
  42. Tao Y, Leteur C, Yang C, Zhang P, Castedo M, Pierre A, Golsteyn RM, Bourhis J, Kroemer G, Deutsch E (2009) Radiosensitization by Chir-124, a selective CHK1 inhibitor: effects of p53 and cell cycle checkpoints. Cell Cycle 8:1196–1205CrossRefPubMedGoogle Scholar
  43. Venkatesha VA, Parsels LA, Parsels JD, Zhao L, Zabludoff SD, Simeone DM, Maybaum J, Lawrence TS, Morgan MA (2012) Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition. Neoplasia 14:519–525CrossRefPubMedPubMedCentralGoogle Scholar
  44. Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M et al (2012) CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res 18:5650–5661CrossRefPubMedPubMedCentralGoogle Scholar
  45. Walton MI, Eve PD, Hayes A, Henley AT, Valenti MR, De Haven Brandon AK, Box G, Boxall KJ, Tall M, Swales K et al (2016) The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Emicro-MYC driven B-cell lymphoma. Oncotarget 7:2329–2342CrossRefPubMedGoogle Scholar
  46. Wehler T, Thomas M, Schumann C, Bosch-Barrera J, Vinolas Segarra N, Dickgreber NJ, Dalhoff K, Sebastian M, Corral Jaime J, Alonso M et al (2017) A randomized, phase 2 evaluation of the CHK1 inhibitor, LY2603618, administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer 108:212–216CrossRefPubMedGoogle Scholar
  47. Weiss GJ, Donehower RC, Iyengar T, Ramanathan RK, Lewandowski K, Westin E, Hurt K, Hynes SM, Anthony SP, McKane S (2013) Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer. Investig New Drugs 31:136–144CrossRefGoogle Scholar
  48. Yang E, William W, Fayette J, Zhang W, Fink A, Lin AB, Deutsch E (2016) Phase Ib trial of LY2606368 in combination with chemoradiation in patients with locally advanced head and neck squamous cell cancer. In: ESMO congress 2016. Ann Oncol 27(Suppl 6):1019TiPGoogle Scholar
  49. Zabludoff SD, Deng C, Grondine MR, Sheehy AM, Ashwell S, Caleb BL, Green S, Haye HR, Horn CL, Janetka JW et al (2008) AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol Cancer Ther 7:2955–2966CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Drug Development UnitThe Institute of Cancer Research and The Royal MarsdenLondonUK

Personalised recommendations