Abstract 3088: Identification of a novel series of MTAP-selective PRMT5 inhibitors, and first disclosure of AZ-PRMT5i-1

Abstract

Abstract Background: PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. Despite this therapeutic potential, there is growing evidence that the first generation of clinical PRMT5 inhibitors may not be able to achieve high clinical efficacy due to PRMT5-driven (e.g. hematological) toxicities. Aims: In order to pharmacologically exploit the MTAP ‘collateral vulnerability’ mechanism for the potential of increased therapeutic index and clinical efficacy, next-generation PRMT5 inhibitors are required to bind PRMT5 in a cooperative manner with natural metabolite methylthioadenosine (MTA). Whilst MTAP-selective PRMT5 inhibitors have recently been reported,1,2,3 there is continued interest in identifying new and structurally diverse in vivo-quality compounds to further investigate this therapeutic opportunity. Results: To identify novel inhibitors of PRMT5 suitable for the MTAP line of sight, our hit finding strategy used a ‘biased’ biochemical high throughput screen of a 2.4M compounds collection. MTA-cooperative hits were validated using techniques including SPR and Xray crystallography. One series identified from this screen was extensively optimized using techniques including structure-based design to improve potency, MTAP selectivity and DMPK properties. Through these optimizations, we have identified AZ-PRMT5i-1, which shows potent in vitro cellular inhibition of PRMT5, over 50-fold MTAP selectivity margin, excellent selectivity against a broad panel of methyltransferases, and suitable oral PK properties. Conclusion: AZ-PRMT5i-1 is a structurally novel and potent PRMT5 inhibitor with high MTAP-selectivity suitable for use in in vitro and in vivo PRMT5-driven models of cancer’. Note: the structure of AZ-PRMT5i-1 will be disclosed at this meeting PRMT5 Cell SDMA: IC50 nM (HCT116 MTAP KO/WT) SDMA MTAP selectivity (fold) LogD/Rat heps CLint/Caco2 intr. A-B HTS hit A 660/4300 6.5 2.1/34/1.6 AZ-PRMT5i-1 5.4/290 54 2.8/5.0/48