In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2721-2721
Abstract:
Checkpoint kinase 1 (Chk1) is a serine/threonine protein kinase that regulates cell division by arresting progression in the S & G2 phases of the cell cycle in response to genotoxic stress. Pharmacological inhibition of Chk1 selectively uncouples the completion of DNA replication from G2/M phase transition in tumor cells lacking parallel cell cycle checkpoint controls, resulting in mitotic catastrophe and cell death. These properties make Chk1 inhibition a unique therapeutic approach as a single agent or as a means to enhance the efficacy of DNA-targeted chemotherapeutic drugs. In this report, we describe our progress in the development of orally bioavailable, potent and selective Chk1 inhibitors derived from an aminopyrazole chemical scaffold. Starting with the lead compound, ONT-2409 (IC50 of & lt;0.1 nM against the Chk1 enzyme), a series of Chk1 inhibitors have been developed. Lead candidates have been generated with potent biochemical IC50s against Chk1 (IC50s = 0.1-0.3 nM). In a panel of 125 protein kinases the top candidates were shown to be highly selective for Chk1, with little appreciable activity against Chk2 or other kinases involved in cell cycle control/DNA damage response. The lead candidates have potent single agent activity against a panel of diverse cancer cell lines (EC50s = 0.03-0.4 μM) and show synergistic enhancement in the activity of clinically relevant DNA targeted chemotherapeutics. Mechanistically, the lead candidates abrogate gemcitabine-induced cell cycle arrest and induce apoptotic cell death. Biomarker studies show the lead candidates inhibit gemcitabine-induced auto-phosphorylation of Chk1 at S296 and reduce phosphorylation of CDK1 at Y15. Compared with ONT-2409, the optimized candidates display improved cell permeability/efflux ratios, superior intrinsic microsomal and hepatic half-lives, and have excellent oral bioavailability in mice and rats. Lead candidate Chk1 inhibitors have also demonstrated potent potentiation of DNA targeted chemotherapies and single agent activity in xenograft tumor models Citation Format: Alex C. Vo, Janelle Taylor, Robert Rosler, Dina Leviten, Teresa Sierra, Richard Boyce, Robert Boyle, Scott Peterson, Kevin Klucher. Discovery and development of orally available subnanomolar potent checkpoint kinase 1 inhibitors as potential anticancer therapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2721.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-2721
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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