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MAT2A
Methionine adenosyltransferase 2α (MAT2A) Inhibitor: Treatment of MTAP Deficient Cancer (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
Developability/CMC
In vitro cell-based
Toxicology studies
Enzymatic
Target Rationale
Methylthioadenosine phosphorylase (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. Methionine adenosyltransferase 2α (MAT2A) is an extra hepatic isoenzyme and has an important role in metabolism and epigenetics as the primary producer of S-adenosylmethionine (SAM) – a molecule involved in cell function and survival. MAT2A is defined as a synthetic lethality target in MTAP deleted cancers. Inhibitors of MAT2A lead to a selective anti-proliferative effect on MTAP deleted cancer cells by reducing the level of SAM to affect PRMT5 dependent mRNA splicing, inducing DNA damage. Inhibition of MAT2A has been indicated as a promising therapeutic strategy for MTAP deleted cancers.
Loss of methylation function of PRMT5 leads to defects in RNA splicing, gene expression and genome integrity
ISM Proprietary
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
Indication
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 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
Insilico Medicine's Pre-Clinical Candidate (PCC) is a potent and selective MAT2A inhibitor. It targets methionine adenosyltransferase 2A (MAT2A) from AI-designed molecules for the treatment of methylthioadenosine phosphorylase (MTAP)-deleted cancers. It demonstrated excellent drug-likeness with good solubility, permeability, activity at low doses in animal models, and a favorable safety profile in preclinical studies.