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Target Overview
PRMT5 is an epigenetic enzyme that catalyzes symmetric dimethylation of arginine (SDMA), controlling multiple cellular processes that drive oncogenesis.1
MTAP deficiency results in accumulation of the metabolite methylthioadenosine (MTA) in tumor cells that induces partial inhibition of PRMT5, rendering these tumors sensitive to PRMT5 inhibition.2-4
MTAP-deficiency is a large opportunity in multiple cancer indications. There are currently no therapeutic options for patients whose tumors are MTAP-deficient.2-4
Compound Overview
AZD3470 is a 2nd-generation, MTAP-selective PRMT5 inhibitor that exploits PRMT5-MTAP collateral vulnerability in MTAP-deficient tumors. AZD3470 preferentially binds in the PRMT5 active site when MTA is present, resulting in selective inhibition of PRMT5 in MTAP deficient tumors and sparing normal tissue.
AZD3470 is in Phase I clinical studies in patients with MTAP-deficient, advanced solid tumors and classical Hodgkin’s lymphoma (cHL).
Mechanism of Action
References
1. Kim H, Ronai ZA. Cell Stress. 2020;4(8):199-215. 2. Kryukov GV, Wilson FH, Ruth JR, et al. Science. 2016;351(6278):1214-1218. 3. Mavrakis KJ, McDonald ER, Schlabach MR, et al. Science. 2016;351(6278):1208-1213. 4. Marjon K, Cameron MJ, Quang P, et al. Cell Rep. 2016;15(3):574-587.
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Abbreviations
cHL
classical Hodgkin’s lymphoma
MTA
methylthioadenosine
MTAP
5′-methylthioadenosine phosphorylase
MTR-1P
methylthioribose-1-phosphate
PRMT5
protein arginine methyltransferase 5
R/R
relapsed/refractory
SDMA
symmetric dimethylation of arginine
Target Overview
PRMT5 is an epigenetic enzyme that catalyzes symmetric dimethylation of arginine (SDMA), controlling multiple cellular processes that drive oncogenesis.1
MTAP deficiency results in accumulation of the metabolite methylthioadenosine (MTA) in tumor cells that induces partial inhibition of PRMT5, rendering these tumors sensitive to PRMT5 inhibition.2-4
MTAP-deficiency is a large opportunity in multiple cancer indications. There are currently no therapeutic options for patients whose tumors are MTAP-deficient.2-4
Compound Overview
AZD3470 is a 2nd-generation, MTAP-selective PRMT5 inhibitor that exploits PRMT5-MTAP collateral vulnerability in MTAP-deficient tumors. AZD3470 preferentially binds in the PRMT5 active site when MTA is present, resulting in selective inhibition of PRMT5 in MTAP deficient tumors and sparing normal tissue.
AZD3470 is in Phase I clinical studies in patients with MTAP-deficient, advanced solid tumors and classical Hodgkin’s lymphoma (cHL).
Mechanism of Action
References
1. Kim H, Ronai ZA. Cell Stress. 2020;4(8):199-215. 2. Kryukov GV, Wilson FH, Ruth JR, et al. Science. 2016;351(6278):1214-1218. 3. Mavrakis KJ, McDonald ER, Schlabach MR, et al. Science. 2016;351(6278):1208-1213. 4. Marjon K, Cameron MJ, Quang P, et al. Cell Rep. 2016;15(3):574-587.
Clinical trial information
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Abbreviations
cHL
classical Hodgkin’s lymphoma
MTA
methylthioadenosine
MTAP
5′-methylthioadenosine phosphorylase
MTR-1P
methylthioribose-1-phosphate
PRMT5
protein arginine methyltransferase 5
R/R
relapsed/refractory
SDMA
symmetric dimethylation of arginine