Author: Couñago, Rafael M. ; Bashore, Frances M. ; Min, Sophia M. ; Howell, Stefanie ; Axtman, Alison D. ; Smith, Jeffery L. ; Popov, Konstantin I. ; Havener, Tammy M. ; Li, Haoxi

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.

01 Jan 2025·Neurobiology of Pain

Targeting Nav1.7 and Nav1.8 with a PIKfyve inhibitor to reverse inflammatory and neuropathic pain

Article

Author: Loya-Lopez, Santiago ; Axtman, Alison D ; Calderon-Rivera, Aida ; Gomez, Kimberly ; Khanna, Rajesh ; Rodríguez-Palma, Erick J ; Min, Sophia M

PIKfyve (1-phosphatidylinositol 3-phosphate 5-kinase), a lipid kinase, plays an important role in generating phosphatidylinositol (3,5)-bisphosphate (PI(3,5)P₂). SGC-PIKFYVE-1, a potent and selective inhibitor of PIKfyve, has been used as a chemical probe to explore pathways dependent on PIKfyve activity. Based on reported changes in membrane dynamics and ion transport in response to PIKfyve inhibition, we hypothesized that pharmacological inhibition of PIKfyve could modulate pain. Acute treatment with SGC-PIKFYVE-1 (10 µM) inhibited voltage-gated sodium currents through the inhibition of Na_v1.7 and Na_v1.8 channels, without affecting voltage-gated calcium or potassium currents in sensory neurons. Additionally, systemic administration of SGC-PIKFYVE-1 (30 mg/kg) alleviated mechanical and cold sensitivity induced by neuropathic or inflammatory pain in both male and female mice, without causing motor impairments. Although other functions of PIKfyve are well characterized, its role in inhibiting chronic pain has not been fully elucidated. Our study provides proof-of-concept for this alternative approach to pain management. Collectively, these results highlight the inhibitory effects of PIKfyve as a promising avenue for further exploration in chronic pain treatment.

13 Oct 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses

Q1 · MEDICINE

Article

Author: McPherson, Peter S. ; Smith, Jeffery L. ; Potjewyd, Frances M. ; Moorman, Nathaniel J. ; Dickmander, Rebekah J. ; Min, Sophia M. ; Heise, Mark ; Howell, Stefanie ; Hossain, Mohammad Anwar ; Axtman, Alison D. ; Bayati, Armin ; Drewry, David H. ; Taft-Benz, Sharon

From a designed library of indolyl pyrimidinamines, we identified a highly potent and cell-active chemical probe (17) that inhibits phosphatidylinositol-3-phosphate 5-kinase (PIKfyve). Comprehensive evaluation of inhibitor selectivity confirmed that this PIKfyve probe demonstrates excellent kinome-wide selectivity. A structurally related indolyl pyrimidinamine (30) was characterized as a negative control that lacks PIKfyve inhibitory activity and exhibits exquisite selectivity when profiled broadly. Chemical probe 17 disrupts multiple phases of the lifecycle of β-coronaviruses: viral replication and viral entry. The diverse antiviral roles of PIKfyve have not been previously probed comprehensively in a single study or using the same compound set. Our scaffold is a distinct chemotype that lacks the canonical morpholine hinge-binder of classical lipid kinase inhibitors and has a non-overlapping kinase off-target profile with known PIKfyve inhibitors. Our chemical probe set can be used by the community to further characterize the role of PIKfyve in virology.

100 Deals associated with SGC-PIKFYVE-1

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Indication	Highest Phase	Country/Location	Organization	Date
Amyotrophic Lateral Sclerosis	Preclinical	United States	The University of North Carolina at Chapel Hill	22 Jan 2025
COVID-19	Preclinical	United States	The University of North Carolina at Chapel Hill	22 Jan 2025
Crohn Disease	Preclinical	United States	The University of North Carolina at Chapel Hill	22 Jan 2025
Rheumatoid Arthritis	Preclinical	United States	The University of North Carolina at Chapel Hill	22 Jan 2025

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