Nicotinamide Phosphoribosyltransferase Inhibitor as a Novel Payload for Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) are a novel modality that allows targeted delivery of potent therapeutic agents to the desired site. Herein we report our discovery of NAMPT inhibitors as a novel nonantimitotic payload for ADCs. The resulting anti-c-Kit conjugates ( and ) demonstrated efficacy in the c-Kit positive gastrointestinal stromal tumor GIST-T1 xenograft model in a target-dependent manner.

Microscale screening of antibody libraries as maytansinoid antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are of great interest as targeted cancer therapeutics. Preparation of ADCs for early stage screening is constrained by purification and biochemical analysis techniques that necessitate burdensome quantities of antibody. Here we describe a method, developed for the maytansinoid class of ADCs, enabling parallel conjugation of antibodies in 96-well format.

3D Pharmacophore Model-Assisted Discovery of Novel CDC7 Inhibitors.

A ligand-based 3D pharmacophore model for serine/threonine kinase CDC7 inhibition was created and successfully applied in the discovery of novel 2-(heteroaryl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-ones. The pharmacophore model provided a hypothesis for lead generation missed by docking to a homology model. Medicinal chemistry exploration of the series revealed clear structure-activity relationships consistent with the pharmacophore model and pointed to further optimization opportunities.

4-(1H-indazol-5-yl)-6-phenylpyrimidin-2(1H)-one analogs as potent CDC7 inhibitors.

A series of 4-(4-hydroxyphenyl)-6-phenylpyrimidin-2(1H)-ones were identified by HTS as inhibitors of CDC7. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus on removing potential metabolic liabilities and improving cellular potency.

CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo.

Purpose: Chk1 kinase is a critical regulator of both S and G(2)-M phase cell cycle checkpoints in response to DNA damage. This study aimed to evaluate the biochemical, cellular, and antitumor effects of a novel Chk1 inhibitor, CHIR124.

Experimental Design: CHIR-124 was evaluated for its ability to abrogate cell cycle checkpoints, to potentiate cytotoxicity, and to inhibit Chk1-mediated signaling induced by topoisomerase I poisons in human tumor cell line and xenograft models.

Development of a screening assay for surrogate markers of CHK1 inhibitor-induced cell cycle release.

Chk1 is a key regulator of the S and G2/M checkpoints and is activated following DNA damage by agents such as the topoisomerase I inhibitor camptothecin (CPT). It has been proposed that Chk1 inhibitors used in combination with such a DNA damaging agent to treat tumors would potentiate cytotoxicity and increase the therapeutic index, particularly in tumors lacking functional p53. The aim of this study was to determine whether gene expression analysis could be used to inform lead optimization of a novel series of Chk1 inhibitors.

3-Benzimidazol-2-yl-1H-indazoles as potent c-ABL inhibitors.

The 3-benzimidazol-2-yl-1H-indazole scaffold was developed as an alternate scaffold for our receptor tyrosine kinase (RTK) inhibitor program. In exploring the SAR of this series, it was discovered that a subset of these compounds potently inhibit the enzyme c-ABL. The SAR of these compounds is described.

4-(Aminoalkylamino)-3-benzimidazole-quinolinones as potent CHK-1 inhibitors.

CHK-1 is one of the key enzymes regulating checkpoints in cellular growth cycles. Novel 4-(amino-alkylamino)-3-benzimidazole-quinolinones were prepared and assayed for their ability to inhibit CHK-1. These compounds are potent cell permeable CHK-1 inhibitors and showed synergistic effect with a DNA-damaging agent, camptothecin.