Development of a Second-Generation, <i>In Vivo</i> Chemical Probe for PIKfyve
We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated <i>in vivo</i> stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, <b>40</b>, and another promising analogue, <b>46</b>. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of <b>40</b> makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition <i>in vivo</i>. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn's disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with <i>in vivo</i> stability.
Authors
- Tammy M. Havener (ORCID: https://orcid.org/0000-0002-4613-0498)
- Alison Donnelly Axtman (ORCID: https://orcid.org/0000-0003-4779-9932)
- Frances M. Bashore (ORCID: https://orcid.org/0000-0003-4241-9873)
- Sophia M. Min (ORCID: https://orcid.org/0000-0001-9840-2996)
- Rafael M. Couñago (ORCID: https://orcid.org/0000-0003-1847-5090)
- Jeffrey L. Smith (ORCID: https://orcid.org/0000-0001-7766-3118)
- Stefanie Howell (ORCID: https://orcid.org/0000-0003-3392-2848)
- Haoxi Li (ORCID: https://orcid.org/0009-0004-8369-1042)
- Konstantin I. Popov (ORCID: https://orcid.org/0000-0002-9394-972X)
Institutions
- University of North Carolina at Chapel Hill (US)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Structural Genomics Consortium (CA)
- Laboratory of Molecular Genetics (PL)
- Drug Discovery Laboratory (Norway) (NO)
- International Centre for Genetic Engineering and Biotechnology (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02531
- Citations
- 6
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 9.75
Funders
- North Carolina Biotechnology Center
- Universidade Estadual de Campinas
- University of North Carolina at Chapel Hill
- NIH Office of the Director
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill