Characterizing the inhibition of PRMT5:MTA by MRTX1719, a clinical stage MTAP-deleted cancer therapeutic
Deletion of the MTAP gene occurs in roughly 15% of human cancers, including (but not limited to) lung, pancreatic, breast, brain, gastrointestinal, prostate, endometrial, melanoma, lymphoma, and leukemia. The protein product of MTAP catabolizes methylthioadenosine (MTA). The absence of this enzyme leads to high levels of MTA in MTAP deleted tumors where MTA can bind to the protein arginine methyl transferase 5 enzyme (PRMT5), displacing the natural cofactor, S-adenosyl methionine (SAM). PRMT5 inhibitors that are selective for the MTA bound form of PRMT5 offer a way around the on-target toxicity of 1st generation PRMT5 inhibitors.
MRTX1719 is currently in first-in-human phase I/II clinical trials for addressing solid tumor cancers with MTAP deletion.
In this study, we characterized the interaction of MRTX1719 with PRMT5 bound to cofactor SAM or MTA using surface plasmon resonance (SPR). PRMT5 is a class II PRMT that catalyzes the sequential and symmetric transfer of methyl groups to arginine residues of substrate proteins thereby epigenetically regulating genes involved in oncogenesis.
However, when characterizing affinities of PRMT5•SAM and PRMT5•MTA, we discovered that the dissociation of the complexes was profoundly too slow to determine using traditional label-free methods. Download the case study to learn about how we developed an SPR chaser assay to overcome this research roadblock, generating IND-enabling data to help MRTX1719 successfully advance to the clinic.
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Netherlands-based Discovery CRO ZoBio was acquired by Oncodesign Services in early 2024. The Oncodesign-ZoBio group contributes to the development of innovative therapies from target to preclinical candidates through stand-alone and integrated capabilities in medicinal chemistry, computer-assisted drug design, protein production, biophysics, structural biology, DMPK, in vitro / in vivo pharmacology, and in vivo pharmaco-imaging.