A Small Molecule Inhibitor of MAT2A as a Potential Treatment of MTAP-/- Cancers (IND-Enabling)
Assays Completed
Owned and Available for Licensing
In vivo efficacy studies
Combo study with Docetaxel
In vivo efficacy studies
with single agent
In vivo PK-PD
In vivo PK studies
In vitro ADMET studies
In vitro cell-based
Toxicology studies
Target Rationale
MTAP-/- frequently occurs in multiple types of cancers including non-small cell lung cancer, bladder cancer and pancreatic cancer and is associated with poor prognosis. MAT2A plays an essential role in metabolism and epigenetics as the primary producer of SAM, the universal methyl donor. SAM is the amino acid methionine bound to an ATP molecule and circulates in the blood and provides methyl groups to maintain other metabolic reactions in cell function and survival.

In MTAP-/- cancer cells, MTAP deletion leads to accumulation of 5'-methylthioadenosine ("MTA") that further inhibits the catalytic activity of PRMT5 and PRMT5 is sensitive to further inhibition by a reduction in SAM levels. Loss of methylation function of PRMT5 leads to defects in RNA splicing, gene expression and genome integrity, which would ultimately lead to cell death. Inhibition of MAT2A leads to reducing the level of SAM, affecting mRNA splicing and inducing DNA damage, and demonstrates a selective anti-proliferative effect on MTAP-/- cancer cell. Thus, MAT2A is a promising therapeutic strategy for MTAP-/- cancers.

Insilico Medicine MAT2A Inhibitor Summary – IND-Enabling
Novel structure generated by AI
  • Distinctly different structure generated by Insilico Medicine's AI small molecule generation platform Chemistry42
Effective in both mono and combo therapies
  • Potent anti-proliferation activity in MTAP deficient Tumors
  • Low efficacious dose in different in-vivo efficacy models for both mono therapy and combinational therapy
Promising drug-ability as an oral agent
  • Favourable drug-likeness property with good solubility and high permeability
  • Promising PK profiles across different preclinical animal species
  • Low drug-drug interaction concerns
Favorable safety margin
  • Favourable in vitro safety profiles
  • Promising safety margin in preclinical studies

MTAP deletion is one of the most common gene deletions seen in cancers including non-small cell lung cancer, bladder, and pancreatic cancer etc., and is associated with poor prognosis, which is found in about 15% of all cancers. MAT2A inhibitors have been shown to reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP deleted cancer cells and tumors.

Project Status – IND-Enabling
A potential best-in-class, orally available small molecule inhibitor of MAT2A, a synthetic lethality target in MTAP deleted, or MTAP-/-, cancers. We are conducting IND-enabling studies for the potential treatment of MTAP-/- Cancers. The preliminary results demonstrated high potency, favorable safety and efficacy profile.

We expect to file an IND application in the second half of 2023 and initiate a Phase I clinical trial shortly after the IND approval in China.

Identified by leveraging our Pharma.AI platform. Through ligand-based drug design of our Generative Chemistry application, we generated multiple hit molecules and with further optimization, the molecule was identified as the preclinical candidate to inhibit MAT2A.
ISM compound at 3 mpk (QD) demonstrated comparable anti-tumor efficacy compared to AG-270 at 100 mpk (QD)