1. Balancing Properties with Carboxylates: A Lead Optimization Campaign for Selective and Orally Active CDK9 Inhibitors.
- Author
-
Tong Y, Florjancic AS, Clark RF, Lai C, Mastracchio A, Zhu GD, Smith ML, Kovar PJ, Shaw B, Albert DH, Qiu W, Longenecker KL, Liu X, Olson AM, Osterling DJ, Tahir SK, Phillips DC, Leverson JD, Souers AJ, and Penning TD
- Abstract
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., Competing Interests: The authors declare the following competing financial interest(s): I'm an employee and stock holder of Abbvie., (© 2021 American Chemical Society.)
- Published
- 2021
- Full Text
- View/download PDF