Highly selective for CDK12, CTX-439 is a first-in-class orally available CDK12 inhibitor.
We believe that inhibition of transcription elongation, an RNA synthesis reaction, induces accumulation of aberrant RNA and produces anti-cancer effects by overloading cancer cells with RNA deregulation stress.
CTX-439 has demonstrated anti-tumor effects in several preclinical carcinoma mouse models as a single agent, and its mechanism of action makes it an attractive potential partner for PARP inhibitors or chemotherapeutic agents targeting DNA replication.
The first step in gene expression is transcription, a process in which DNA sequence information is copied into RNA.
This transcription process is carried out by an enzyme called RNA polymerase (Pol II).
Abnormalities in the transcriptional response may induce accumulation of aberrant RNA, leading to RNA deregulation stress.
The C-terminal domain (CTD) of Pol II consists of a characteristic structure of seven amino acid sequences, Tyr(1)-Ser(2)-Pro(3)-Thr(4)-Ser(5)-Pro(6)-Ser(7), repeated 52 times.
This CTD is phosphorylated by diverse kinases and is responsible for the initiation, elongation, and termination steps of transcription.
Phosphorylation of the second Ser(2) of CTD is known to be most closely associated with the regulation of transcriptional elongation, and we are focusing on the kinase responsible for this phosphorylation modification to the second Ser(2) of CTD.
CDK12 belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases.
CDK12 forms a complex with cyclin K and phosphorylates the second Ser(2) of the CTD of Pol II, which is known to promote the elongation step in the transcription reaction, especially for transcripts such as BRCA1 and BRCA2 that are involved in DNA damage response.
Therefore, inhibition of CDK12 is expected to have a synergistic effect with PARP inhibitors and chemotherapeutic agents, since it leads to decreased expression of a group of factors involved in the DNA damage response as well as DNA damage.
