image: Based on the structure and binding mode of existent molecules, Insilico’s R&D team used Chemistry42, the small molecule generation and design platform integrating more than 40 generative models, to generate more than 3,600 candidate molecules guided by predefined characteristics including novelty, privileged fragments, diversity and drug-likeness.
Credit: Insilico Medicine
Among the cyclin-dependent kinases (CDKs), CDK8 and CDK19 regulate signal-induced, context-specific transcription reprogramming and play key roles in cell proliferation and differentiation. As previous studies have noted, the inhibition of CDK8/19 could suppress cancer cell proliferation and metastasis, thus posing a potential therapy for hematological and solid cancers, including acute myeloid leukemia (AML), breast cancer, colorectal cancer and prostate cancer.
Clinical-stage generative artificial intelligence (AI)-driven drug discovery company Insilico Medicine (“Insilico”) announced a novel small molecule CDK8/19 inhibitor designed using the proprietary generative chemistry platform Chemistry42. The lead compound not only exhibits strong enzymatic activity and selectivity, but also shows favorable ADME properties and oral bioavailability in multiple animal models. The development process and validation results were recently published in the Journal of Medicinal Chemistry.
Based on the structure and binding mode of existent molecules, Insilico’s R&D team used Chemistry42, the small molecule generation and design platform integrating more than 40 generative models, to generate more than 3,600 candidate molecules guided by predefined characteristics including novelty, privileged fragments, diversity and drug-likeness. Later the researchers initiated virtual screening through protein-ligand interaction analysis, which enabled further structural optimization and produced the candidate lead compound.
“Starting from known compounds, we used Chemistry42 for higher efficiency in structural modification exploration and substitution selection, in order to generate molecules that satisfy our drug-likeness, synthetic accessibility and novelty requirements,” says Zhen Wang, a co-first author of the paper and computational chemistry scientist at Insilico Medicine. “With the help of Chemistry42, we can focus on the optimization of compound activity and molecular properties, thus accelerating the drug discovery and development process.”
According to the validation results, the lead compound demonstrated selectivity against CDK8/19 over known molecules, nanomolar tumor inhibitory potency, and low risk of drug-drug interactions (DDIs). In addition, preclinical tests in multiple animal models have shown improved pharmacokinetic (PK) properties, as well as antitumor activity in AML, breast cancer, and lymphoma.
“This is another potential lead compound efficiently generated by Insilico with the help of the Chemistry42 platform, and the positive preclinical data can support subsequent studies,” says Xiao Ding, PhD, vice president and head of Chemistry & DMPK of Insilico Medicine. “In mice models, the lead compound demonstrated potent efficacy as a potential treatment for a wide range of cancers, either as monotherapy and combination therapy.”
Insilico is a pioneer in using generative AI for drug discovery and development, and has been making groundbreaking progresses in multiple disease areas, including fibrosis, cancer, immunology and aging-related disease. Since 2021, Insilico has nominated 18 preclinical candidates in its comprehensive portfolio of over 30 assets and has advanced eight molecules to the clinical stage. In March 2024, the Company published a paper in Nature Biotechnology that discloses the raw experimental data and the preclinical and clinical evaluation of its lead drug – a potentially first-in-class TNIK inhibitor for the treatment of idiopathic pulmonary fibrosis discovered and designed using generative AI currently in Phase II trials with patients.
About Insilico Medicine
Insilico Medicine, a global clinical-stage biotechnology company powered by generative AI, connects biology, chemistry, and clinical trial analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers, and other modern machine learning techniques for novel target discovery and generating novel molecular structures with desired properties. Insilico Medicine is developing breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system diseases, infectious diseases, autoimmune diseases, and aging-related diseases. www.insilico.com
Journal
Journal of Medicinal Chemistry
Article Title
Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of Cancer
Article Publication Date
1-May-2024