Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers

  • J Med Chem. 2023 Dec 14;66(23):15629-15647. doi: 10.1021/acs.jmedchem.3c01233.
David B Freeman  1  2 ,  Tamara D Hopkins  1  2 ,  Peter J Mikochik  1  2 ,  Joseph P Vacca  1  2 ,  Hua Gao  1  2 ,  Adel Naylor-Olsen  3 ,  Sonali Rudra  4 ,  Huixu Li  5 ,  Marius S Pop  1  2 ,  Rosa A Villagomez  1  2 ,  Christina Lee  1  2 ,  Heng Li  1  2 ,  Minyun Zhou  1  2 ,  Douglas C Saffran  1  2 ,  Nathalie Rioux  6 ,  Tressa R Hood  1  2 ,  Melinda A L Day  1  2 ,  Michael R McKeown  1  2 ,  Charles Y Lin  1  2 ,  Norbert Bischofberger  1  2 ,  B Wesley Trotter  1  2
Affiliations
  • 1. Kronos Bio, Inc., 301 Binney Street, 2nd Floor East, Cambridge, Massachusetts 02142, United States.
  • 2. Kronos Bio, Inc., 1300 So. El Camino Real Suite 400, San Mateo, California 94402, United States.
  • 3. Naylor Olsen Consulting, LLC, 3369 Saddle Wood Court, Lansdale, Pennsylvania 19446, United States.
  • 4. TCG Lifesciences Private Limited, Block BN, Plot 7, Salt-lake Electronics Complex, Sector V, Kolkata 700091, West Bengal, India.
  • 5. WuXi AppTec (Tianjin) Co., Ltd., 168 NanHai Road, 10th Avenue, TEDA, Tianjin 300457, P. R. China.
  • 6. Certara Strategic Consulting, 100 Overlook Center, Suite 101, Princeton, New Jersey 08540, United States.
PMID: 37967851 DOI: 10.1021/acs.jmedchem.3c01233
Abstract

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 Inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

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