Abstract A235: Structure-guided evolution of potent and selective oral inhibitors of CHK1 through scaffold morphing.
Authors: Matthews Thomas P. , Klair Suki , Cheung Kwai-Ming J. , Scanlon Jane , Lainchbury Michael , Piton Nelly , Fisher Martin , Cherry Michael , Boxall Kathy , Walton Michael I. , Westwood Isaac M. , Hayes Angela , Eve Paul , Valenti Melanie , de Haven Brandon Alexis , Box Gary , van Montfort Rob L. M. , Williams David H. , Aherne Wynne , Raynaud Florence I. , Eccles Suzanne A. , Garrett Michelle D. , Reader John C. , Collins Ian 
Published: June 2012

Abstract
The DNA damage response network ensures the fidelity of DNA replication and controls the repair of damage arising during cellular replication or from exogenous agents such as genotoxic drugs. Checkpoint Kinase 1 (CHK1) is a serine/threonine kinase occupying a central position in this complex network of cell regulatory and DNA repair mechanisms. G1/S, S or G2/M cell cycle checkpoints are activated in response to genotoxic antitumor drugs to provide an opportunity for repair of damaged DNA or to activate apoptotic pathways. Unlike normal cells, human cancer cells frequently have functional defects in the tumor suppressor p53 with consequent loss of G1/S checkpoint control and greater reliance on S and G2/M checkpoints. Thus CHK1 inhibitors which abrogate the S and G2/M checkpoints will selectively sensitize p53 deficient cancer cells to DNA damaging agents. CHK1 inhibition by siRNA and several small molecule inhibitors have confirmed this in preclinical studies.
The challenges of improving the CHK1 potency and selectivity of our initial, fragment derived pyrazolopyridine inhibitors, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps. Initial hit compounds were optimised into potent inhibitors of CHK1 using iterative cycles of design, synthesis, assay and crystallography, progressing through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and isoquinolines. The potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, and potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts when dosed i.p. in nude mice. Further lead optimisation led to orally bioavailable analogues with good in vitro ADME and in vivo pharmacokinetic properties, exemplified by CCT244747. CCT244747 has demonstrated both in vivo pharmacodynamic modulation of signaling through CHK1 and potentiation of cytotoxic drugs in human tumor xenografts.
In summary, we show how a fragment derived compound with weak, micromolar activity against CHK1 evolved through a scaffold hopping strategy to give the selective CHK1 isoquinoline inhibitor SAR-020106, from which optimisation of pharmacokinetic properties led to potent, selective and orally bioavailable CHK1 inhibitors such as CCT244747.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A235.