BGB-58067 is an oral, potent, brain-penetrant, MTA-cooperative inhibitor of protein arginine methyltransferase 5 (PRMT5) being developed for advanced solid tumors with homozygous MTAP deletion.1
BGB-58067 is currently being evaluated as monotherapy in a first-in-human Phase 1a/b study with enrollment restricted to MTAP-deficient tumors.1
Conventional noncooperative PRMT5is inhibit PRMT5 activity in both tumor and normal cells, leading to dose-limiting hematologic toxicity and a narrow therapeutic index. MTA-cooperative PRMT5 inhibition preferentially suppresses PRMT5 activity in MTAP-deleted tumor cells while sparing normal tissues.1
BGB-58067 was designed to selectively bind the (PRMT5_MTA complex, enabling tumor-selective PRMT5 inhibition. Preclinical data demonstrate inhibition of PRMT5-mediated signaling and in vivo antitumor activity in MTAP-deficient models, supporting translation into a biomarker-selected clinical population.1
Safety and efficacy have not been established for investigational products and/or uses. The clinical relevance of nonclinical data has not been established.
MTA, methylthioadenosine; MTAP, S-methyl-5’-thioadenosine phosphorylase; PRMT5, protein arginine methyltransferase 5.
PRMT5 is a type II arginine methyltransferase responsible for symmetric dimethylarginine (SDMA) modification of histone and nonhistone substrates involved in transcription, RNA splicing, DNA damage repair, apoptosis, and cell cycle regulation.1,2
MTAP is homozygously deleted in approximately 15% of human cancers, resulting in intracellular accumulation of MTA. Elevated MTA partially suppresses PRMT5 activity, creating a selective vulnerability to further PRMT5 inhibition and establishing a well-validated synthetic lethal relationship between MTAP loss and PRMT5 dependence.1,3,4
In MTAP-deleted tumor cells, accumulated MTA stabilizes the PRMT5-MTA complex, which is selectively inhibited by BGB-58067. This results in suppression of PRMT5-mediated symmetric dimethylarginine (SDMA) formation, leading to disruption of RNA splicing, transcriptional regulation, DNA repair, and cell cycle progression.1
In the ongoing Phase 1 study, dose-dependent modulation of SDMA has been incorporated as a pharmacodynamic endpoint to assess on-mechanism PRMT5 inhibition in patients.1
CNS, central nervous system; DNA, deoxyribonucleic acid; MTA, methylthioadenosine; MTAP, S-methyl-5’-thioadenosine phosphorylase; PRMT5, protein arginine methyltransferase 5; RNA, ribonucleic acid; SMDA, symmetric dimethylarginine.
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