2. Academic Validation
  3. Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve

Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve

  • J Med Chem. 2025 Feb 13;68(3):3282-3308. doi: 10.1021/acs.jmedchem.4c02531.
Sophia M Min 1,  Frances M Bashore 1,  Jeffery L Smith 1,  Tammy M Havener 1,  Stefanie Howell 1,  Haoxi Li 2,  Rafael M Couñago 1 3,  Konstantin I Popov 4,  Alison D Axtman 1
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 Laboratory for Molecular Modeling, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Center of Medicinal Chemistry (CQMED), Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas, UNICAMP, Campinas, SP 13083-886, Brazil.
  • 4 Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 39838960 DOI: 10.1021/acs.jmedchem.4c02531
Abstract

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 in vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, 40, and another promising analogue, 46. 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 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. 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 in vivo stability.

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