Discovery of Gut-Restricted PRMT5 Inhibitors to Intercept Colorectal Cancer in Patients with Genetic Loss of Tumor Suppressor Adenomatous Polyposis Coli
Loss of the functional Adenomatous Polyposis Coli (<i>APC</i>-LOF) tumor suppressor gene represents the disease-initiating event in most colorectal cancer (CRC) cases. A newly identified dependency between PRMT5 and <i>APC</i>-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 <b>9</b> and <b>18</b>, displaying low absorption in preclinical species and high first-pass extraction mediated by aldehyde oxidase. <b>9</b> and <b>18</b> demonstrated in vivo colon pharmacodynamics without signs of systemic on-target toxicity, confirming gut-restriction. Administering <b>9</b> to dextran sodium sulfate (DSS)-treated polyp-bearing <i>Apc</i><sup>Min/+</sup> mice significantly reduced polyp number, indicating local treatment efficacy.
Authors
- Jan Willem Thuring (ORCID: https://orcid.org/0000-0003-4154-1586)
- Fabian Hulpia (ORCID: https://orcid.org/0000-0002-7470-3484)
- Petra Vinken
- Wim Schepens (ORCID: https://orcid.org/0000-0002-4915-6773)
- Tammy L. Bush
- Cynthia Milligan
- Zhengyu Jiang (ORCID: https://orcid.org/0000-0002-4788-9068)
- Zienab Etwebi
- Stefaan Last
- Aaron Patrick (ORCID: https://orcid.org/0009-0002-8971-0158)
- Susan Lepri (ORCID: https://orcid.org/0000-0003-1024-7368)
- Sven Van Brandt (ORCID: https://orcid.org/0000-0002-7140-8869)
- Carla S. Veríssimo (ORCID: https://orcid.org/0000-0001-8589-3300)
- Ferran Jardí
- Juan‐Miguel Jimenez
- Eileen D. Vesely (ORCID: https://orcid.org/0009-0002-8239-0219)
- Mariana Teixeira da Silva (ORCID: https://orcid.org/0000-0002-1979-6219)
- Serge Pieters
- Albi Francis
- Guido Verniest (ORCID: https://orcid.org/0000-0002-4682-5054)
- Egor M. Larin (ORCID: https://orcid.org/0000-0003-4986-1373)
- Joseph E. Leenaerts
- Yi Fan (ORCID: https://orcid.org/0000-0001-6199-6778)
- Jie Yang (ORCID: https://orcid.org/0000-0002-2240-8504)
- Kurtis E. Bachman (ORCID: https://orcid.org/0000-0001-5387-6207)
- Ferdinand H. Lutter (ORCID: https://orcid.org/0000-0001-8588-1692)
- Johan Nicolaï (ORCID: https://orcid.org/0000-0001-5479-0085)
- Laura Pérez‐Benito (ORCID: https://orcid.org/0000-0001-9607-9048)
- Mark S. Hixon (ORCID: https://orcid.org/0000-0002-3525-0654)
- Bethany K. Mattson
- Gauri A. Patwardhan
- Xuemei Yao (ORCID: https://orcid.org/0000-0002-2284-1906)
- Dana S. Gaffney (ORCID: https://orcid.org/0009-0006-0236-8089)
- Alexandra G. Liddane (ORCID: https://orcid.org/0009-0003-1724-3877)
- Sylvia F. Boj (ORCID: https://orcid.org/0000-0002-6910-1083)
- David J. Pocalyko (ORCID: https://orcid.org/0000-0002-4815-723X)
- Victoria D. Wong
- Gerben ten Hag
- Kathleen W. Clancy (ORCID: https://orcid.org/0000-0003-0425-2689)
- Evelien Renders
- Yufei Wang (ORCID: https://orcid.org/0000-0002-2317-9010)
- Fei Chen (ORCID: https://orcid.org/0000-0003-3895-6318)
- José Périto Leite Rodrigues da Silva (ORCID: https://orcid.org/0000-0001-7285-8282)
- Siyu Li (ORCID: https://orcid.org/0000-0001-7233-7903)
- Melissa Everaerts
- Shuai Jin
- M. da G. da C. Carvalho
- Gerald Chu (ORCID: https://orcid.org/0009-0008-6407-8057)
- Claudia Thäte
- Dan Lv
- Irene Vetrano
- Constance Smith-Monroy
- Froylan Omar Fernandez Candelaria (ORCID: https://orcid.org/0000-0001-8074-1404)
- Ed Retzbach
- Hans Sterckx
- Remco Zijlmans
Institutions
- Johnson & Johnson (United States) (US)
- Jilin Province Tumor Hospital (CN)
- Pharmaron (United Kingdom) (GB)
- Translational Research in Oncology (FR)
- Johnson & Johnson (Israel) (IL)
- Drug Discovery Laboratory (Norway) (NO)
- Association of Organ Procurement Organizations (US)
- AstraZeneca (Germany) (DE)
- Intercept Pharmaceuticals (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00830
- Citations
- 1
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.81