December 3, 2024, Abbisko Therapeutics Co., Ltd. (HKEX: 02256) today announced that the US FDA has cleared the IND application for ABSK131, a highly-selective small molecule inhibitor of PRMT5*MTA. A phase 1 clinical study in patients with advanced solid tumors will be conducted under the title “A Phase 1, First-in-Human, Multicenter, Open-Label Study of ABSK131 to Assess Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy in Patients with Advanced/Metastatic Solid Tumors”. The study population will primarily consist of patients with MTAP gene deficiency.

Approximately 15% of solid tumors lack expression of methylthioadenosine phosphorylase (MTAP), a tumor suppressor gene ^[1]. Solid tumors with high rates of MTAP deficiency include non-small cell lung cancer (NSCLC) (15.7%), pancreatic cancer (21.7%), esophageal cancer (28.4%), mesothelioma (32.2%), and gastrointestinal cancer (10.4% of gastric and 1% of colorectal cancer)^[2], of which mesotheliomas and pancreatic cancers have no approved targeted therapies.

MTAP encodes a key rate-limiting enzyme in the metabolism of polyamines and purines and plays a major role in the purine/methionine salvage pathway^[3]. MTAP deficiency causes accumulation of its substrate methylthioadenosine (MTA) that inhibits protein arginine methyltransferase 5 (PRMT5) ^[4]. PRMT5 is an enzyme that catalyzes the symmetrical transfer of two methyl groups from S-adenosyl methionine (SAM) to arginine residues on proteins, influencing various physiological processes, including transcription, RNA splicing, ribosome biogenesis, and cell cycle regulation ^[5-6]. PRMT5 has been found to exhibit synthetic lethality in MTAP-deficient tumors ^[7-9]. Recent studies have demonstrated that selectively targeting PRMT5*MTA shows promise as a therapeutic strategy for MTAP-deficient cancers.

About ABSK131
ABSK131 is a novel, small molecule MTA-cooperative PRMT5 inhibitor with strong anti-tumor activity being developed by Abbisko Therapeutics. In preclinical studies, ABSK131 demonstrated excellent selectivity for MTAP-deleted cancer cells, as well as favorable drug metabolism and pharmacokinetic properties for oral dosing.

References:

1.     Kalev P, Hyer ML, Gross S, et al. MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage. Cancer Cell. 2021;39(2):209-224.e11. doi:10.1016/j.ccell.2020.12.010

2.     Bertino JR, Waud WR, Parker WB, Lubin M. Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies. Cancer Biol Ther. 2011;11(7):627-632. doi:10.4161/cbt.11.7.14948.

3.     de Menezes WP, Silva VAO, Gomes INF, Rosa MN, Spina MLC, Carloni AC, et al. Loss of 5′-methylthioadenosine phosphorylase (MTAP) is frequent in high-grade gliomas; nevertheless, it is not associated with higher tumor aggressiveness. Cells. 2020;9(2):492.

4.     Bray C, Balcells C, McNeish IA, Keun HC. The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality. Front Oncol. 2023;13:1264785. Published 2023 Sep 19. doi:10.3389/fonc.2023.1264785.

5.     Blanc RS, Richard S. Arginine Methylation: The Coming of Age. Mol Cell. 2017;65(1):8-24.

6.     Kim H, Ronai ZA. PRMT5 function and targeting in cancer. Cell Stress. 2020;4(8):199-215.

7.     Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A, Marlow SE, et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016;351(6278):1214-8.

8.     Marjon K, Cameron MJ, Quang P, Clasquin MF, Mandley E, Kunii K, et al. MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell Rep. 2016;15(3):574-87.

9.     Mavrakis KJ, McDonald ER, 3rd, Schlabach MR, Billy E, Hoffman GR, deWeck A, et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science. 2016;351(6278):1208-13.