CDK12

Cyclin-dependent kinase 12/13 (CDK12/13) Inhibitor:

Treating Tumors through Induction of BRCAness

(IND-Enabling)

Assays Completed

Wholly-owned and Available for Licensing

• In vivo efficacy studies – Combo study with Olaparib and Cisplatin
• In vivo efficacy studies – Single agent
• In vivo PK-PD
• In vivo PK studies
• In vitro ADMET studies
• Developability/CMC
• In vitro cell-based
• Toxicology studies
• Enzymatic

Target Rationale

Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases. The CDK12/cyclin K complex regulates the elongation step of RNA transcription by phosphorylating Ser2 on the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II, and selectively affects the expression of genes such as BRCA1 and BRCA2, involved in DNA Damage Response (DDR). Inhibition or loss of CDK12/CDK13 provokes a "BRCAness" phenotype that results in deficiencies in DNA damage repair, promoting synergy with DNA-damaging chemotherapy and PARP inhibitors.

CDK12 inhibition causes a BRCAness phenotype by blocking homologous recombination.

Cancer Cell 2019; Nov 11; 36:1-14

Insilico Medicine CDK12 Inhibitor Summary – IND-Enabling

Novel structure generated by AI

• Novel structure generated by Insilico Medicine's AI small molecule generation platform Chemistry 42
• Effective in both mono and combo therapies
  • Potent anti-proliferation activity in BRCAm and beyond BRCAm TNBC tumors
  • Potential broader indications such as AML, HCC, SCLC, Colorectal cancer, and Ovarian cancer
• Promising drug-ability as an oral agent
  • Good in vitro ADME profiles
  • Promising PK profiles across different preclinical animal species
• Significantly higher safety margin
  • Promising safety margin in rat DRF studies
  • Excellent in vitro safety profiles, such as hERG, CYP, Ames

Indications

• Triple negative breast cancer (TNBC)

  CDK12 knockdown impairs cell growth and tumorigenesis of TNBC, which is an unmet medical need

• Colorectal cancer (CRC)
  CDK12 inhibitors may be effective in the treatment of CRC, especially in BRAF mutant and mesenchymal CRCs with poor prognosis

• Ovarian cancer
  Ovarian cancer is associated with a high frequency of HRD. CDK12 works as a synthetic lethal target with HRD or DNA-crosslinking agents

• Hepatocellular carcinoma (HCC)
  CDK12 knockdown and inhibition impaired the cell growth and tumorigenesis of HCC and showed synergy with sorafenib in sorafenib resistant lines

Project Highlight

Insilico Medicine developed an AI-designed covalent inhibitor targeting CDK12. In vivo efficacy studies in SUM149PT CDX mice models showed strong dose-dependent anti-tumor activity with robust and durable tumor regression. The data also indicated that the inhibitor could induce BRCAness in the tumor cells.

Insilico Medicine's (ISM) compound showed strong anti-tumor activity with robust and durable tumor regression.