ENPP1

Ectonucleotide phosphodiesterase 1 (ENPP1) Inhibitor: Treating anti-PD-1/-L1 resistant cancers

Current Stage: IND Clearance

Wholly-owned and Available for Licensing

Indication

ICB (Immune Checkpoint Blockade) works in only 10-30% of all cancer patients. In colorectal cancer (CRC), PD-1/-L1 antibodies are efficacious in MSI-high patients, which make up around 15% of CRC tumors. Up to 80% of CRC is microsatellite stable (MSS) and considered to be chromosomally unstable (CIN+). Tumors with high chromosome instability generate micronuclei, the rupture of which releases DNA into the cytosol, which is sensed by cGAS, leading to the production of the anti-tumor STING pathway activator, cGAMP. ENPP1 (which hydrolyses cGAMP, thus suppressing STING activation) is often highly expressed in these tumors and correlates with poor patient outcomes and resistance to anti PD-1/PD-L1 antibodies.

By driving STING pathway activity, inhibition of ENPP1 may therefore represent a useful treatment for a subset of anti-PD-1/L-1 resistant tumors that exhibit reduced tumor T cell activity and infiltration.

The combination of ENPP1 inhibitors with anti-PD-1/PD-L1 antibodies has great potential in immuno-oncology.

Combination therapy with anti-PD-1/PD-L1 antibodies:

• ENPP1 inhibitor as a tumor microenvironment modulator resulted in increased T cell infiltration into solid tumors
• Enhanced efficacy for anti-PD-1/PD-L1 antibodies in both MSS and MSI-h cancers

About ISM5939

According to preclinical data, ISM5939 demonstrated robust anti-tumor efficacy in in vivo studies, while showing favorable safety profile, as well as in vitro ADMET and in vivo pharmacokinetic profiles.

Insilico utilized proprietary generative AI engines affiliated to Pharma.AI to accelerate the early development of ISM5939, obtaining the lead compound within 3 months of project initiation.

Assays Completed

Enzymatic

Toxicology studies

In vitro cell-based

Developability/CMC

In vitro ADMET studies

In vivo PK studies

In vivo PK-PD

In vivo efficacy studies with single agent

In vivo efficacy studies

Combo study with anti-PD-1, or anti-PD-L1