1. Academic Validation
  2. Discovery of Gut-Restricted PRMT5 Inhibitors to Intercept Colorectal Cancer in Patients with Genetic Loss of Tumor Suppressor Adenomatous Polyposis Coli

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.
Fabian Hulpia 1 Wim Schepens 1 Susan Lepri 1 Johan Nicolaï 2 Zhengyu Jiang 3 Sylvia F Boj 4 Tammy L Bush 3 Mary-Ambre Carvalho 1 Falian Chen 5 Gerald Chu 6 Kathleen W Clancy 7 Zienab Etwebi 8 Melissa Everaerts 9 Yi Fan 7 Froylan Omar Fernandez Candelaria 7 Albi Francis 3 Mark S Hixon 10 Ferran Jardi 2 Shuai Jin 5 Egor M Larin 11 Stefaan Last 1 Joseph E Leenaerts 1 Siyu Li 5 Alexandra G Liddane 8 Ferdinand H Lutter 11 Dan Lv 5 Bethany Mattson 3 Cynthia M Milligan 12 Aaron N Patrick 7 Gauri Anand Patwardhan 7 Laura Perez-Benito 13 Serge Pieters 1 Evelien Renders 1 Ed Retzbach 8 Constance Smith-Monroy 7 José Silva 14 Mariana Silva 4 Hans Sterckx 9 Gerben Ten Hag 4 Claudia Thäte 2 Sven Van Brandt 1 Carla S Verissimo 4 Guido Verniest 11 Eileen Vesely 8 Irene Vetrano 1 Petra Vinken 2 Yufei Wang 1 Victoria Wong 7 Xuemei Yao 5 Jie Yang 5 Remco Zijlmans 1 Kurtis E Bachman 8 David Pocalyko 8 Juan-Miguel Jimenez 1 Dana Gaffney 8 Jan Willem Thuring 1
Affiliations

Affiliations

  • 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.
Abstract

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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