Discovery of Gut-Restricted PRMT5 Inhibitors to Intercept Colorectal Cancer in Patients with Genetic Loss of Tumor Suppressor Adenomatous Polyposis Coli
- J Med Chem. 2025 Aug 26. doi: 10.1021/acs.jmedchem.5c00830.
- 1. Global Discovery Chemistry, Therapeutics Discovery (TD), DPDS, Janssen Pharmaceutica NV, Johnson & Johnson Innovative Medicine, Beerse B-2340, Belgium.
- 2. Preclinical Safety and Translational Sciences (PSTS), DPDS, Janssen Pharmaceutica NV, Johnson & Johnson Innovative Medicine, Beerse B-2340, Belgium.
- 3. Tumor Biology, US Biology Oncology, Johnson & Johnson Innovative Medicine, Springhouse,Pennsylvania 19477, United States.
- 4. HUB Organoids B.V., Utrecht 3584, The Netherlands.
- 5. Pharmaron Beijing Co. Ltd. Beijing 100176, P. R. China.
- 6. Oncology Translational Research, Johnson & Johnson Innovative Medicine, Springhouse, Pennsylvania 19477, United States.
- 7. Discovery Technologies and Molecular Pharmacology (DTMP), Therapeutics Discovery (TD), DPDS, Johnson & Johnson Innovative Medicine, Springhouse, Pennsylvania 19477, United States.
- 8. CRC Interception Discovery, US Biology Oncology, J&J Innovative Medicine, Springhouse, Pennsylvania 19477, United States.
- 9. Discovery Pharmaceutics, DPDS, Johnson & Johnson Innovative Medicine, Beerse B-2340, Belgium.
- 10. Preclinical Safety and Translational Sciences (PSTS), DPDS, Johnson & Johnson Innovative Medicine, La Jolla, California 92121-1126, United States.
- 11. Discovery Process Research, DPDS, Janssen Pharmaceutica NV, Johnson & Johnson Innovative Medicine, Beerse B-2340, Belgium.
- 12. Structural and protein Sciences, Therapeutics Discovery (TD), DPDS, Johnson & Johnson Innovative Medicine, Springhouse, Pennsylvania 19477, United States.
- 13. In Silico Discovery, Therapeutics Discovery (TD), DPDS, Janssen Pharmaceutica NV, Johnson & Johnson Innovative Medicine, Beerse B-2340, Belgium.
- 14. Preclinical Safety and Translational Sciences (PSTS), DPDS, Johnson & Johnson Innovative Medicine, Springhouse, Pennsylvania 19477, United States.
Loss of the functional Adenomatous Polyposis Coli (APC-LOF) tumor suppressor gene represents the disease-initiating event in most colorectal Cancer (CRC) cases. A newly identified dependency between PRMT5 and APC-LOF suggests that inhibiting PRMT5 may help intercept CRC. To circumvent hematological toxicities associated with orally bioavailable first-generation PRMT5 inhibitors, we aimed to limit systemic exposure after oral administration. We describe our efforts, challenges, and compound evaluation workflow resulting in gut-restricted PRMT5 inhibitors. A two-pronged approach was envisioned, consisting of (1) minimizing passive absorption, and (2) maximizing systemic clearance by incorporation of a metabolic "soft spot". This resulted in 9 and 18, displaying low absorption in preclinical species and high first-pass extraction mediated by aldehyde oxidase. 9 and 18 demonstrated in vivo colon pharmacodynamics without signs of systemic on-target toxicity, confirming gut-restriction. Administering 9 to dextran sodium sulfate (DSS)-treated polyp-bearing APCMin/+ mice significantly reduced polyp number, indicating local treatment efficacy.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: Histone MethyltransferaseResearch Areas: Cancer