Open AccessBalancing Properties with Carboxylates: A Lead Optimization Campaign for Selective and Orally Active CDK9 Inhibitors
Author(s) -
Yunsong Tong,
Alan S. Florjancic,
Rick F. Clark,
Chunqiu Lai,
Anthony Mastracchio,
GuiDong Zhu,
Morey L. Smith,
Peter Kovar,
Bailin Shaw,
Daniel H. Albert,
Wei Qiu,
K.L. Longenecker,
Xiaoqin Liu,
Amanda M. Olson,
Donald J. Osterling,
Stephen K. Tahir,
Darren C. Phillips,
Joel D. Leverson,
Andrew J. Souers,
Thomas D. Penning
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00161
Subject(s) - cyclin dependent kinase 9 , pharmacophore , kinase , pharmacology , cyclin dependent kinase , toxicity , chemistry , dosing , serine , protein kinase a , biology , biochemistry , enzyme , cyclin dependent kinase 2 , cell cycle , cell , organic chemistry
Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration. Here, we report the lead optimization of a series of azaindole-based inhibitors. To overcome early challenges with promiscuity and cardiovascular toxicity, carboxylates were introduced into the pharmacophore en route to compounds such as 14 and 16 . These CDK9 inhibitors demonstrated a reduced toxicity, adequate pharmacokinetic properties, and a robust in vivo efficacy in mice upon oral dosing.