The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.

Members of the Bromodomain and Extra-Terminal (BET) family of bromodomain-containing proteins (BRD2, BRD3, BRD4, and BRDT) bind to acetylated lysine residues on histone tails and act as epigenetic readers to regulate chromatin structure and gene expression. In particular, BET family member BRD4 has been shown to positively regulate the expression of MYC and other critical cancer-associated genes through the localization of BRD4 to super-enhancer regulatory elements. Results from preclinical studies conducted using the small molecule tool BET inhibitor (+)-JQ1, and emerging data from clinical trials of BET inhibitors in leukemia and lymphoma patients, have provided support for the therapeutic potential of BET inhibitors in hematologic malignancies.

Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4 +/- 0.6 nM, Akt cell potency of 50 +/- 19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po). (C) 2008 Elsevier Ltd. All rights reserved.

The synthesis and biological evaluation of potent and selective inhibitors of the erbB2 kinase is presented. Based on the 4-anilinoquinazoline chemotype, the syntheses of several new series of erbB2 inhibitors are described with quinazoline and pyrido[4,3-d]pyrimidine cores. The vast majority of these compounds are found to be >100x selective over the closely related EGFR kinase. Two lead compounds are further shown to have low clearance and moderate bioavailability in rat.