Novel CDK12/13 small molecule inhibitor a preclinical candidate for multiple tumours

18 Oct 2023
Novel CDK12/13 small molecule inhibitor a preclinical candidate for multiple tumours

Cyclin-dependent kinase 12 (CDK12) is an important transcription-associated member of the CDK family.

It shows versatile roles in regulating gene transcription, RNA splicing, translation, and intronic polyadenylation.

Increasing evidence has demonstrated the critical role of CDK12 in various human cancers as both a biomarker of cancer and a potential target for cancer therapy.

A research team utilised AI-driven indication explorations and compared the omics data between tumour and normal tissues in over 90 disease-specific datasets across different cancers, and merged the consideration from text-based analysis tools containing clinical trials, grants, and publications.

Subsequently, the target identification function ranked target prioritisation associated with indications by the feature scores based on different algorithms like matrix factorisation, causal inference, and de novo pathway reconstruction, pointing to a strong causal association between CDK12 and a wide of cancer indications including triple-negative breast cancer (TNBC), lung cancer, colorectal cancer, and pancreatic cancer.

After determining the target, researchers designed a series of compounds for CDK12 using the generative AI small molecule engine Chemistry42, and nominated ISM9274 as the preclinical candidate at the end of August 2023.

In in vitro studies, ISM9274 has demonstrated potent antiproliferative activities in more than 60 cancer cell lines in 13 tumour categories, especially in triple-negative breast cancer, pancreatic cancer, and other urgent clinical needs with limited therapies.

ISM9274 showed robust in vivo efficacy in multiple xenograft models for both monotherapy and combo-therapy.

Moreover, the molecule has a favourable safety profile and ADME properties.

“As potential targets, CDK12/13 poses not only opportunities, but also challenges,” said Feng Ren, PhD, co-CEO and Chief Scientific Officer of Insilico Medicine.

“With its robust efficacy in a variety of indications as well as satisfactory safety margins in preclinical studies, we believe that ISM9274, a novel CDK12/13 inhibitor, offers potential breakthroughs to unmet clinical needs in oncology. ISM9274 is now being progressed to IND-enabling studies and we plan to submit an IND application in the second half of 2024.”

Source: Insilico Medicine