Biotechnology company Insilico Medicine has unveiled a new study showcasing how the company’s advanced generative AI platform and integrated workflow helped to identify and validate ENPP1 as a critical immune checkpoint among multiple solid tumours, which helped to the development of a highly specific oral ENPP1 inhibitor, ISM5939.  

The study, published in Nature, details how researchers utilised Insilico’s AI-driven target discovery, PandaOmics, alongside multi-omic patient data to screen and rank indications most likely to respond to ENPP1 inhibitors. These indications include triple-negative breast cancer (TNBC), hepatocellular carcinoma (liver cancer), acute myeloid leukemia, ovarian cancer, colorectal adenocarcinoma, breast cancer, head and neck cancer, and ER-negative breast cancer.  

Using single-cell sequencing data and spatial transcriptomics, the team confirmed that elevated ENPP1 expression is associated with an immunosuppressive tumour microenvironment across tumour types, suggesting ENPP1 inhibition can remodel “immune desert”-like tumour microenvironments into more highly immune-infiltrated and inflammatory microenvironments. 

Researchers then leveraged generative chemistry AI facilitate the design of novel ENPP1 inhibitors. The researchers used a structure-based drug design approach to generate new compounds from scratch selected for features like predicted activity, synthetic accessibility, and structural novelty, efficiently obtaining hit molecules within three months.  

The top candidate compounds were optimised and through iterative refinement, ISM5939 emerged as a promising compound with drug-like properties, demonstrating high selectivity and potency for ENPP1 inhibition. 

Preclinical data indicates that ISM5939 functions effectively in combination with multiple therapies, potentiating the effects of existing cancer treatments by modulating immune responses and enhancing therapeutic efficacy.  

When combined with anti-PD-1 therapy, ISM5939 synergistically amplifies T-cell activity and boosts antitumour immunity. In combination with chemotherapy, ISM5939 increases cGAMP accumulation in the tumour microenvironment, thereby activating the STING pathway in antigen-presenting cells (APCs) and improving chemotherapy efficacy. Similarly, when used alongside PARP inhibitors, ISM5939 further enhances STING activation, driving stronger antitumour immune responses. Moreover, ISM5939 exhibits a higher safety margin compared with direct STING agonists, with no significant induction of pro-inflammatory cytokines in the peripheral blood and no triggering of effector T cell death within the tumour microenvironment. 

“In this study, Insilico Medicine fully showcased the deep integration of biology, computational science, and AI-driven drug discovery and design, providing entirely new possibilities for cancer immunotherapy,” said Feng Ren, Co-CEO and Chief Scientific Officer of Insilico Medicine. “We hope the publication of the ISM5939 discovery process in Nature Communications will inspire the industry, accelerate the discovery of next-generation innovative drugs, unleash the potential of STING-targeted therapies, and bring more new options to immunotherapy.”