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Abstract: PO1305

Small Molecule APOL1 Inhibitors Block APOL1 Pore Function and Reduce Proteinuria in an APOL1-Mediated Kidney Disease Mouse Model

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Zimmerman, Brandon, Vertex Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Dakin, Leslie, Vertex Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Fortier, Anne, Vertex Pharmaceuticals Inc, Boston, Massachusetts, United States

Two genetic variants of APOL1 (G1 and G2) are associated with increased risk of kidney diseases. Current treatment options for APOL1-mediated kidney diseases are limited and do not address the underlying cause of disease. Here, we report the discovery of a series of novel small molecule APOL1 inhibitors, including the clinical candidate VX-147, that block APOL1 function in vitro and reduce proteinuria in a transgenic mouse model of kidney disease.


Microscale thermophoresis was used to assess binding of small molecule APOL1 inhibitors to recombinant APOL1 protein. HEK293 cells overexpressing APOL1 variants were used to quantify inhibition of APOL1-mediated cell death and ion flux. In addition, activity on APOL1 biological function was assessed using a trypanosome viability assay. Finally, changes in proteinuria following APOL1 inhibitor administration were assessed using a transgenic mouse model homozygous for the APOL1 G2 variant (G2Hom).


Small molecule APOL1 inhibitors showed binding to all three forms of APOL1 (wild-type, G1 and G2 variants). In cellular assays, APOL1 inhibitors prevented APOL1-mediated HEK293 cell death and inhibited APOL1-mediated ion flux. Addition of APOL1 inhibitors to trypanosome cultures rescued the parasites from APOL1-induced killing. The potency of VX-147 was consistent across the in vitro functional assays described above (EC50 of approximately 2nM). Finally, administration of IFNγ in G2Hom mice induced APOL1 expression, resulting in elevated urine albumin-to-creatinine ratios. Oral administration of VX-147 reduced proteinuria in IFNγ-induced APOL1 G2Hom mice by 74.1%.


Novel small molecule APOL1 inhibitors, including VX-147, bind recombinant APOL1 protein and inhibit its biological function, as demonstrated by trypanosome parasite rescue. These inhibitors block APOL1 pore function, as demonstrated by reduced APOL1-induced death and APOL1-induced ion flux of tetracycline-inducible APOL1 HEK293 cells. Administration of APOL1 inhibitors reduced APOL1-dependent proteinuria in an APOL1-mediated transgenic mouse model of kidney diseases. Taken together, our results strongly suggest small molecule APOL1 inhibitors, such as VX-147, target the underlying cause of disease, and have the potential to treat APOL1-mediated kidney diseases.