Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease

Brandon Zimmerman (), Leslie A. Dakin, Anne Fortier, Evanthia Nanou, Angelo Blasio, James Mann, Howard Miller, Marissa Fletcher, Tiansheng Wang, Suganthini Nanthakumar, Gizelle McCarthy, Caline Matar, Prachi Matsye, Guanyu Wang, Phillip Snyder, Kevin Daniel, Harsha Swamy, Kelly Sullivan, Franklin Bright, Audrey Powers, Kevin J. Gagnon, Fan Lu, Steven Paula, Suvarna Khare-Pandit, Larry Henry, Martine Hamel, Francois Denis, Olivier Nicolas, Niresh Hariparsad, Shyamesh Kumar, Jennifer Proctor, Timothy Senter, Brinley Furey and Mark E. Bunnage ()
Additional contact information
Brandon Zimmerman: Vertex Pharmaceuticals Incorporated
Leslie A. Dakin: Vertex Pharmaceuticals Incorporated
Anne Fortier: Vertex Pharmaceuticals Incorporated
Evanthia Nanou: Vertex Pharmaceuticals Incorporated
Angelo Blasio: Vertex Pharmaceuticals Incorporated
James Mann: Vertex Pharmaceuticals Incorporated
Howard Miller: Vertex Pharmaceuticals Incorporated
Marissa Fletcher: Vertex Pharmaceuticals Incorporated
Tiansheng Wang: Vertex Pharmaceuticals Incorporated
Suganthini Nanthakumar: Vertex Pharmaceuticals Incorporated
Gizelle McCarthy: Vertex Pharmaceuticals Incorporated
Caline Matar: Vertex Pharmaceuticals Incorporated
Prachi Matsye: Vertex Pharmaceuticals Incorporated
Guanyu Wang: Vertex Pharmaceuticals Incorporated
Phillip Snyder: Vertex Pharmaceuticals Incorporated
Kevin Daniel: Vertex Pharmaceuticals Incorporated
Harsha Swamy: Vertex Pharmaceuticals Incorporated
Kelly Sullivan: Vertex Pharmaceuticals Incorporated
Franklin Bright: Vertex Pharmaceuticals Incorporated
Audrey Powers: Vertex Pharmaceuticals Incorporated
Kevin J. Gagnon: Vertex Pharmaceuticals Incorporated
Fan Lu: Vertex Pharmaceuticals Incorporated
Steven Paula: Vertex Pharmaceuticals Incorporated
Suvarna Khare-Pandit: Vertex Pharmaceuticals Incorporated
Larry Henry: Vertex Pharmaceuticals Incorporated
Martine Hamel: Vertex Pharmaceuticals Incorporated
Francois Denis: Vertex Pharmaceuticals Incorporated
Olivier Nicolas: Vertex Pharmaceuticals Incorporated
Niresh Hariparsad: Vertex Pharmaceuticals Incorporated
Shyamesh Kumar: Vertex Pharmaceuticals Incorporated
Jennifer Proctor: Vertex Pharmaceuticals Incorporated
Timothy Senter: Vertex Pharmaceuticals Incorporated
Brinley Furey: Vertex Pharmaceuticals Incorporated
Mark E. Bunnage: Vertex Pharmaceuticals Incorporated

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Chronic kidney disease affects ~10% of people worldwide and there are no disease modifying therapeutics that address the underlying cause of any form of kidney disease. Genome wide association studies have identified the G1 and G2 variants in the apolipoprotein L1 (APOL1) gene as major contributors to a subtype of proteinuric kidney disease now referred to as APOL1-mediated kidney disease (AMKD). We hypothesized that inhibition of APOL1 could have therapeutic potential for this genetically-defined form of kidney disease. Here we describe the development of preclinical assays and the discovery of potent and specific APOL1 inhibitors with drug-like properties. We provide evidence that APOL1 channel activity drives podocyte injury and that inhibition of this activity stops APOL1-mediated cell death and kidney damage in a transgenic mouse model. These preclinical data, combined with clinical data from our previously published phase 2 proof-of-concept study, support the potential of APOL1 channel inhibition for the treatment of AMKD.

Date: 2025
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DOI: 10.1038/s41467-024-55408-2

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