# MTAP-MAT2A synthetic-lethality induced by transition state analogs

> **NIH CA R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2026 · $692,197

## Abstract

Methylthioadenosine phosphorylase (MTAP) uniquely recycles methylthioadenosine (MTA) in humans,
maintaining near zero MTA concentrations. The discovery that MTAP-deleted (MTAP-/-) tumors are uniquely
sensitive to co-deletion of MAT2A or PRMT5 has led to intense interest in targeting MAT2A and PRMT5, a new
synthetic-lethal approach to cancer therapy. Over a dozen clinical trials with MAT2A and/or PRMT5 inhibitors
target 15% of human tumors that are MTAP-/-. However, only 1% of colorectal cancers (CRC) are MTAP-/-,
excluding CRC patients from all these trials, along with 85% of all cancer patients with MTAP+/+ tumors. Drugs
targeting MAT2A and PRMT5 are effective only when MTA is elevated in MTAP-/- tumors, but pharmacological
MTAP inhibition can convert MTAP+/+ tumors to the MTAP-/- phenotype. We developed MTAP transition state
analog inhibitors with picomolar efficacy and their prodrugs to optimize pharmacodynamics. Our MTAP inhibitors
are highly specific, non-toxic agents that recapitulate the MTAP-/- phenotype in otherwise isogenic cells. MTAP
inhibitors mimic genetic inactivation of MTAP-/- tumors, increasing both systemic and tumor MTA levels. Efficacy
of these inhibitors was demonstrated in in multiple systems, and synthetic lethality with MAT2A or PRMT5
inhibitors was demonstrated . Therefore, combined inhibition of MTAP with MAT2A or PRMT5 opens CRC
patients and other MTAP+/+ patients to ongoing clinical trials by this synthetic-lethal therapy. The mechanism
impinges on PRMT5 inhibition. PRMT5 uses S-adenosylmethionine (SAM) to methylate 60 or more downstream
regulatory proteins linked to inhibition of cancer cell growth. MAT2A inhibitors block SAM synthesis. MTA is a
powerful inhibitor of PRMT5 and current-generation PRMT5 inhibitors require elevated tumor MTA for efficacy.
Thus, the synergy among MTAP, MAT2A and PRMT5 inhibitors, also provides potential for dose de-escalation
for these drugs in clinical trials to minimize reported toxicity.
 We established 

## Key facts

- **NIH application ID:** 11294877
- **Project number:** 1R01CA300091-01A1
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** LEONARD H AUGENLICHT; WINFRIED  EDELMANN; Vern L. Schramm
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $692,197
- **Award type:** 1
- **Project period:** 2026-05-01T00:00:00 → 2031-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11294877

## Citation

> US National Institutes of Health, RePORTER application 11294877, MTAP-MAT2A synthetic-lethality induced by transition state analogs (1R01CA300091-01A1). Retrieved via AI Analytics 2026-07-05 from https://api.ai-analytics.org/grant/nih/11294877. Licensed CC0.

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