4 research outputs found
The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer
A class of 2-acyliminobenzimidazoles has been developed
as potent and selective inhibitors of anaplastic lymphoma kinase (ALK).
Structure based design facilitated the rapid development of structure–activity
relationships (SAR) and the optimization of kinase selectivity. Introduction
of an optimally placed polar substituent was key to solving issues
of metabolic stability and led to the development of potent, selective,
orally bioavailable ALK inhibitors. Compound <b>49</b> achieved
substantial tumor regression in an NPM-ALK driven murine tumor xenograft
model when dosed qd. Compounds <b>36</b> and <b>49</b> show favorable potency and PK characteristics in preclinical species
indicative of suitability for further development
Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
Tankyrases
(TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP)
family. They have been shown to directly bind to axin proteins, which
negatively regulate the Wnt pathway by promoting β-catenin degradation.
Inhibition of tankyrases may offer a novel approach to the treatment
of <i>APC</i>-mutant colorectal cancer. Hit compound <b>8</b> was identified as an inhibitor of tankyrases through a combination
of substructure searching of the Amgen compound collection based on
a minimal binding pharmacophore hypothesis and high-throughput screening.
Herein we report the structure- and property-based optimization of
compound <b>8</b> leading to the identification of more potent
and selective tankyrase inhibitors <b>22</b> and <b>49</b> with improved pharmacokinetic properties in rodents, which are well
suited as tool compounds for further in vivo validation studies