Biochemical kinase assays revealed that HMN-384 potently inhibits CDK11 kinase activity with an IC50 of . To assess selectivity, HMN-384 was screened against a panel of 468 kinases using the KinomeScan assay at a concentration of 1 µM. HMN-384 demonstrated exquisite selectivity, with a selectivity score (S(35)) of 0.01. Notably, HMN-384 showed >1,000-fold selectivity over CDK4 and CDK6, and >500-fold selectivity over CDK9. This distinct selectivity profile suggests that HMN-384 avoids the neutropenia and gastrointestinal toxicity associated with CDK4/6 and CDK9 inhibition, respectively. 2.2. Cellular Mechanism of Action We evaluated the antiproliferative activity of HMN-384 across a panel of breast cancer cell lines. HMN-384 exhibited potent cytotoxicity in TNBC lines (MDA-MB-231, BT-549) with GI50 values ranging from 12 to 28 nM, whereas luminal breast cancer lines (MCF-7, T47D) were significantly less sensitive. Malena Movie Telegram Link Upd Today
In this study, we describe , a potent and highly selective inhibitor of CDK11. We present the chemical synthesis, structure-activity relationship (SAR), and comprehensive preclinical evaluation of HMN-384, demonstrating its efficacy as a novel therapeutic agent for TNBC. 2. Results 2.1. Discovery and Biochemical Characterization of HMN-384 Through structure-based drug design (SBDD) utilizing the crystal structure of the CDK11/Cyclin L complex, we synthesized a series of aminopyrimidine derivatives optimized for interaction with the unique "gatekeeper" residue of CDK11. This effort yielded HMN-384 ((2R)-2-[[4-[(3-chlorophenyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methylbutan-1-ol). Adobe Master Collection Cc 2017 Update 3 Patc... - 3.79.94.248
HMN-384: A Novel, Potent, and Selective Small-Molecule Inhibitor of CDK11 with Antitumor Activity in Preclinical Models of Triple-Negative Breast Cancer
Recent genomic and proteomic analyses have identified CDK11 (cyclin-dependent kinase 11) as a critical dependency in TNBC. CDK11 exists as two isoforms, CDK11A and CDK11B, encoded by distinct genes but sharing a conserved kinase domain. CDK11 plays a pivotal role in pre-mRNA splicing and transcriptional regulation, often forming a complex with Cyclin L. Unlike CDK4/6, CDK11 is essential for the survival of cancer cells with high transcriptional burdens, acting as a non-oncogene addiction factor.
The mechanism of action of HMN-384 is distinct from current standards of care. By inhibiting CDK11, HMN-384 disrupts the transcription-splicing axis, a vulnerability particularly pronounced in the "transcriptionally addicted" TNBC subtype. The induction of intron retention suggests that cancer cells cannot tolerate the loss of CDK11-mediated RNA processing, leading to apoptotic cell death. This mechanism provides a rationale for the use of HMN-384 in tumors that have developed resistance to CDK4/6 inhibitors via Rb loss or Cyclin E amplification.