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Abstract: FR-PO946

Mechanistic Evaluation and In Vivo Validation of a Novel HIPK2 Inhibitor as Anti-Fibrosis Therapy for Kidney Disease

Session Information

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Lee, Kyung, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
  • Feng, Ye, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
  • Chen, Yibang, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
  • Beresis, Richard Thomas, ChemPartner Co., San Francisco, California, United States
  • Drakas, Robert, Rila Therapeutics Inc., San Francisco, California, United States
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
Background

HIPK2 is a multifaceted kinase that potentiates key pathways implicated in CKD pathogenesis (i.e., TGF-β/Smad3, NF-κB, Wnt/β-catenin, and p53 signaling). Substantial experimental evidence indicates the renoprotective effects of HIPK2 loss. Since global HIPK2 KO mice are viable, fertile, and without overt defects, HIPK2 is considered an optimal druggable target for CKD and fibrosis. However, some oncogenic concerns remained with p53 inactivation with HIPK2 loss. We recently developed a small molecule HIPK2 inhibitor (HIPK2i) that allosterically inhibits HIPK2-Smad3 interaction without altering its kinase activity. It effectively and selectively mitigated TGF-β/Smad3 signaling in kidney tubular cells and kidney fibrosis, without affecting p53. Based on this parental HIPK2i molecule, we have developed superior HIPK2i analogs, including HIPK2i-174, with improved physicochemical properties with acceptable safety profiles. We examined the specific pathways inhibited by HIPK2i-174 in tubular cells and its effects in vivo.

Methods

We examined HIPK2i-174-affected gene expression by RNA sequencing and its effects on Smad3 phosphorylation and protein-protein interaction by IP/MS analysis in kidney cells. To expand the in vivo efficacy profile of HIPK2i-174, we have narrowed the effective dose range of HIPK2i-174 in Tg26 HIVAN model of CKD. We also examined the effects of concurrent treatment of ACE inhibitor, Ramipril, and HIPK2i-174 in Col4a3-deficient Alport syndrome mice.

Results

RNAseq analysis confirmed that HIPK2i-174 treatment effectively and selectively blocked TGF-β signaling in primary kidney tubular cells. HIPK2i-174 affected Smad3 phosphorylation and decreased its activity. It inhibited Smad3's interaction with several proteins including TAK, Ezrin, and EIF3F following TGF-β stimulation. In vivo, 30mg/kg dose of HIPK2i-174 was equally effective in attenuating proteinuria and fibrosis in Tg26 mice in comparison to higher doses (60 and 90mg/kg), and concurrent treatment of Ramipril and HIPK2i-174 in Col4a3-deficient Alport syndrome mice showed synergistic renoprotective effects with improved survival rate.

Conclusion

New HIPK2i-174 demonstrates favorable drug-like properties, safety profiles, and in vivo efficacy in CKD models, indicating its potential as a novel anti-fibrosis therapy in CKD.

Funding

  • Commercial Support