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

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.

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

“…Although 14 sacrifices the high selectivity to CDK9, its inhibitory potency is significantly enhanced compared to that of 50 . In xenograft mouse models of prostate cancer and acute myeloid leukemia, the tumor growth inhibition (TGI) rate of 14 reaches 82%. , Currently, it has progressed to the clinical trial stage (NCT04718675).…”

Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation

“…While the remaining 20% form complexes with Cyclin T2A, Cyclin T2B, or Cyclin K. CDK9 expression has been found to be dysregulated in various types of cancer. − Inhibition of CDK9 results in transient transcriptional suppression and preferential depletion of apoptosis-related proteins with short half-lives, such as Mcl-1, c-Myc, and XIAP. So far, several selective CDK9 inhibitors have entered clinical research successively for the treatment of malignant hematological tumors such as acute myeloid leukemia (AML), including AZD4573, VIP152, KB-0742, et al (Figure ), and most of the design concepts of CDK9 inhibitors are focused on CDK subtype selectivity and properties suitable for achieving short target engagement. , Recent studies have shown that MYC gene mutations and abnormal Mcl-1 expression are also one of the main factors driving the onset and metastasis of CRC in addition to malignant hematological tumors. − Therefore, targeting CDK9 might work as an appealing strategy for treating CRC. In this work, we preliminarily demonstrated the feasibility of CDK9 as a potent target of treatment for colorectal cancer, and a novel CDK9 inhibitor, named CLZX-205, was designed and synthesized, which possessed acceptable pharmacokinetic properties and antitumor efficacy in vitro and in vivo.…”