CDK12/13 inhibition by CTX-439 creates a targetable BCL-2/BCL-xL dependency

ABSTRACT: CDK12/13 regulate transcription through phosphorylation of Serine 2 (S2) in the C-terminal domain of RNA polymerase II and have emerged as potential therapeutic targets in cancer. Here, we report the development of CTX-439, an orally bioavailable, ATP-competitive small-molecule inhibitor of CDK12/13. CTX-439 inhibits S2 phosphorylation and downregulates genes involved in DNA damage repair, resulting in antitumor activity in vitro and in vivo, including in breast cancer patient-derived xenograft models. A CRISPR activation screen identified the anti-apoptotic BCL-2 family members BCL-2 and BCL-xL as mediators of resistance to CTX-439. Accordingly, combined inhibition of CDK12/13 and BCL-2/BCL-xL induced apoptosis and enhanced tumor growth suppression in xenograft models. Mechanistically, CT

SUBMITTER: Hiroko Yamakawa 

PROVIDER: S-SCDT-10_1038-S44321-026-00549-8 | biostudies-other |

REPOSITORIES: biostudies-other