Development of retinoid nuclear receptor pathway antagonists through targeting aldehyde dehydrogenase 1A3
Aldehyde dehydrogenase 1a3 (ALDH1A3) activity is recognized as a pathogenic trait in cardiometabolic diseases and cancer, though the mechanisms by which ALDH1A3 promotes disease are unclear and effective therapeutic inhibitors of ALDH1A3 are lacking. Whereas the function of the ALDH1A enzymes in development is the conversion of retinaldehyde into all-<i>trans</i> retinoic acid (atRA) to activate retinoid nuclear receptor signaling, this pathway is paradoxically hypothesized as a cell-intrinsic tumor suppressor pathway. We resolve this paradox by showing that while ALDH1A3 is overexpressed across diverse cancers, ALDH1A3-expressing tumor cells lose sensitivity to retinoid signaling. Instead, atRA produced by ALDH1A3 acts in a paracrine fashion to activate retinoid nuclear receptor signaling in immune cells to suppress anti-tumor immunity. To inhibit ALDH1A3, we developed a hybrid <i>in silico</i> and high-throughput screening approach followed by medicinal optimization to identify first-in-class, oral and safe antagonists of ALDH1A3 with potent anti-tumor immunotherapeutic activity and an optimized drug development profile.
Authors
- John Proudfoot (ORCID: https://orcid.org/0000-0002-5922-2228)
- Claudia Beato (ORCID: https://orcid.org/0000-0003-3917-0843)
- Yan Pan (ORCID: https://orcid.org/0009-0006-3445-8265)
- Alfonso Pozzan
- Josiah E. Hutton (ORCID: https://orcid.org/0000-0002-5518-9651)
- Yibin Kang (ORCID: https://orcid.org/0000-0002-1626-6730)
- Ileana M. Cristea (ORCID: https://orcid.org/0000-0002-6533-2458)
- Maureen A. Kane (ORCID: https://orcid.org/0000-0002-5525-9170)
- Xiaoyang Su (ORCID: https://orcid.org/0000-0001-8081-1396)
- Mark Esposito (ORCID: https://orcid.org/0000-0002-5724-4087)
- Jianshi Yu (ORCID: https://orcid.org/0000-0002-4666-2435)
- Tavis J. Reed (ORCID: https://orcid.org/0000-0002-0945-5461)
- Muthiah A. Manoharan (ORCID: https://orcid.org/0000-0002-7931-1172)
- Wen Wang (ORCID: https://orcid.org/0000-0003-4120-0773)
- Fang Cao (ORCID: https://orcid.org/0000-0002-4451-1481)
- X. Cheng (ORCID: https://orcid.org/0009-0000-7225-1499)
- Xiang Hang
- Yong Wei (ORCID: https://orcid.org/0000-0003-3019-2173)
- Enrico D Perini
Institutions
- University of Maryland, Baltimore (US)
- Princeton University (US)
- WuXi AppTec (China) (CN)
- Discovery Institute (US)
- Johnson University (US)
- Community Health Systems - Lutheran Hospital (US)
- Aptuit (Italy) (IT)
- Ludwig Cancer Research (US)
- SciGenom Labs (India) (IN)
Publication Details
- Journal
- iScience
- Published
- 2025-10-04
- DOI
- https://doi.org/10.1016/j.isci.2025.113675
- Citations
- 2
- Primary Topic
- Retinoids in leukemia and cellular processes
- Type
- article
- Field-Weighted Citation Impact
- 1.61