image: ISM6631 is a potent pan-TEAD non-covalent inhibitor with a novel scaffold developed from Chemistry42. view more
Credit: Insilico Medicine
- Based on the novel scaffold generated by Chemistry42, ISM6331 is a highly novel molecule with best-in-class potential.
- Being a pan-TEAD inhibitor, ISM6331 has shown potent efficacy at a low dose, as well as favorable safety profile and DMPK properties.
- Guided by structure-based drug design strategies, potential candidates were generated with a clustering method and ranked through the Chemistry42 scoring and reward pipelines.
Insilico Medicine ("Insilico"), a generative artificial intelligence (AI)-driven clinical-stage drug discovery company, today announced the nomination of ISM6331, a potential best-in-class pan-TEAD inhibitor, as a preclinical candidate compound (PCC) generated by Chemistry42, its proprietary generative chemistry-driven molecule design engine, targeting the Hippo pathway for the treatment of advanced solid tumors.
Transcriptional enhanced associate domain (TEAD) proteins, a family including TEAD1-4 transcription factors, are recognized to be key transcription factors of the Hippo pathway, and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. By interacting with upstream oncogenic signaling pathways and controlling downstream target genes, TEAD has emerged as a potential therapeutic target for cancer treatment and options against drug resistance, with multiple novel therapies in development.
ISM6631 is a potent pan-TEAD non-covalent inhibitor with a novel scaffold developed from Chemistry42, Insilico’s proprietary generative AI platform for molecule design and optimization. In preclinical studies, it shows broad anti-tumor effect in multiple cell lines and potent efficacy at low doses in animal models. It also demonstrates favorable oral bioavailability and high safety margin. The promising preclinical data will further support Insilico's R&D team to advance the program to the clinical stage.
“We are pleased to nominate ISM6331, a novel pan-TEAD inhibitor, as a potential solution for drug resistance in solid tumor patients,” said Feng Ren, PhD, Co-CEO and Chief Scientific Officer of Insilico Medicine. “TEAD showed ideal pocket size and shape cavity, which is convenient for us to utilize Chemistry42 to generate molecules in the structure-based drug discovery strategy from a structural point of view. In this case, our scientists efficiently found the hit compound targeting TEAD in the first round of generation. We are committed to advancing the clinical translation of this program to bring innovative therapies to meet unmet medical needs.”
Insilico’s R&D team utilized the comprehensive database of Chemistry42, composed a generative model starting with TEAD1 crystal structure, and blended in TEAD 2-4 structure properties including pharmacophore for the generation of pan-TEAD inhibitors. More than 6,000 molecules were generated and clustered into 6 series, among which 7 molecules were synthesized and tested, yielding 3 promising hit series in the first round. Based on the affinity score, novelty score, and reward information provided by Chemistry42, a lead compound was acquired in the second round through molecular docking and other optimization methods, leading to ISM6331.
“The novelty and best-in-class potential of ISM6331 is a perfect demonstration of Insilico’s AI capabilities, given that the molecule is based on the novel scaffold generated by Chemistry42,” said Alex Zhavoronkov, PhD, Founder and CEO of Insilico Medicine. “Insilico has the advantage of being a specialist in not only chemistry, but also biology and clinical studies, and we are ready to progress more pipelines efficiently in the future, with the power of AI and robotics.”
Since it was founded in 2014, Insilico has been leading breakthroughs at the intersection of advanced technologies, including artificial intelligence, generative chemistry, generative biology, and quantum computing, and presenting to the public through academic papers and drug R&D progress. Recently, Insilico presented at BIO International 2023, the world’s largest biotechnology gathering, with its comprehensive portfolio of over 30 programs, including 3 clinical assets, as well as showcasing its integrated AI drug discovery platform, Pharma.AI.
About Insilico Medicine
Insilico Medicine, a clinical stage end-to-end generative artificial intelligence (AI)-driven drug discovery company, is connecting biology, chemistry, and clinical trials 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 the generation of 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.
Website: www.insilico.com