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
  • 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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