Selective CDK12 inhibitors & synthetic lethality
Dr Bert Klebl, Lead Discovery Center GmbH; Dr Axel Choidas, Lead Discovery Center GmbH
Lead Discovery Center GmbH
CDK12 is a cyclin-dependent kinase (CDK) of the family of CDK-homologs spanning at least 21 different CDKs and further CDK-like enzymes in humans. CDKs play a major role in regulating the progression through the cell cycle. Whereas a subclass of CDKs (CDK8, CDK9, CDK12 and CDK13) is responsible for regulating transcription through phosphorylation of C-terminal domain of RNA polymerase II. These are known as transcriptional CDKs and show strong links to cancer formation.
Literature indicates the involvement of CDK12 in DNA damage repair mechanisms and linked mutated CDK12 to high-grade serous ovarian carcinoma (HGS-OvCa) rendering it a potentially good drug target. Especially with the success of PARP inhibitors, validating the concept of synthetic lethality, DNA damage repair processes have most recently experienced increasing interest for therapeutic interventions. Interestingly, literature demonstrating synergism between CDK12 inhibitors and PARP Inhibitors is accumulating recently.
However, the pivotal role of CDKs and its complex regulation demands for highly selective inhibitors to avoid undesired adverse effects. Non-specific first-generation CDK-inhibitors resulted in toxicity issues and the lack of a therapeutic window in clinical trials and thus shifted the focus to the optimization on selective small molecule CDK inhibitors. The clinical success of the first highly selective CDK inhibitors, the CDK4/6 inhibitor (palbociclib) and LDC's CDK9 inhibitor (atuveciclib) licensed to Bayer, has re-fueled interest in CDKs and particular in the development of highly selective CDK inhibitors.
The aim of this project is the development of lead compounds selectively inhibiting CDK12 and CDK13 (collectively named CDK12).
CDK12 is a cyclin-dependent kinase that is involved in the cell cycle management/governance/control and specifically impacts the regulation of transcription by phosphorylating the C-terminal domain of RNA polymerase II. Impairment of CDK12 has been correlated to several cancers such as high-grade serous ovarian carcinoma.
The project is in late Hit-to-Lead stage and benefits from LDC’s world-class expertise in generating highly selective and potent kinase inhibitors as emphasized by the successfully partnered CDK9 and CDK7 programs.
Lynparza, AstraZeneca’s and Merck & Co’s PARP inhibitor, reached $1 billion in sales in 2019 and Pfizer’s Ibrance (palbociclib) topped $2 billion demonstrating not only the high medical need, but also the commercial potential.
Ibrance in combination with an aromatase inhibitor resulted in a median of 19.1 months of progression-free survival (PFS) in women with HR-positive, HER2-negative breast cancer based on real world evidence. The reference group receiving aromatase inhibitor alone had 11.9 months (PFS) emphasizing the benefit to patients.
A rationale drug discovery approach based on a focused kinase library screen in combination with structure-based design has been conducted. We have identified novel inhibitors of CDK12, which are currently undergoing profiling in vivo as well as medchem-based and structure-guided optimization.
A composition of matter patent application will be filed upon in vivo proof-of-concept with our Lead series of CDK12 inhibitors.
Lui, G. Y., Grandori, C., & Kemp, C. J. (2018). CDK12: an emerging therapeutic target for cancer. Journal of clinical pathology, 71(11), 957-962.
Quereda, V., Bayle, S., Vena, F., Frydman, S. M., Monastyrskyi, A., Roush, W. R., & Duckett, D. R. (2019). Therapeutic targeting of CDK12/CDK13 in triple-negative breast cancer. Cancer cell, 36(5), 545-558.