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