Abstract: PO2474
A Novel Allosteric HIPK2 Inhibitor Attenuates Renal Fibrosis with Superior Pharmacokinetic, Selectivity, and Safety Profiles
Session Information
- CKD: Inflammation, Endothelial Dysfunction, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Feng, Ye, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Chen, Ya, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Beresis, Richard Thomas, ChemPartner, South San Francisco Innovation Center, San Francisco, California, United States
- Drakas, Robert, ShangPharma Innovations Inc., San Francisco, California, United States
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background
Renal fibrosis is considered the final convergent pathway for progressive CKD, regardless of the original etiologies of the disease. Although much has been learned of the molecular mechanisms underlying renal fibrogenesis, there is still a paucity of success in translating this knowledge to clinical application. We previously demonstrated HIPK2 as a multifunctional activator of TGF-β/Smad3, NF-κB, and p53 pathways and that the global knockout of HIPK2 in mice attenuated kidney fibrosis in vivo. We recently developed a small molecule inhibitor of HIPK2, BT173, that specifically blocked TGF-β/Smad3 pathway to attenuate renal fibrosis without causing adverse systemic effects. Importantly, BT173 did not alter the activity of p53 to produce unwanted oncogenic side effects. However, the in vivo use of BT173 was limited by its poor solubility and potency.
Methods
Based on BT173, we used iterative cycles of chemical synthesis and biological assays to optimize the solubility, bioavailability and potency of TGF-β/Smad3 pathway inhibition. ADME, selectivity, and safety profiling were performed on the optimized HIPK2 inhibitor compounds. The lead inhibitor was then tested in CKD models to test its efficacy in reducing renal fibrosis.
Results
1) Repeated iteration and in vitro screening assay led to a lead compound, HIPK2i-174. 2) HIPK2i-174 showed greater potency (IC50<200nM) to disrupt the HIPK2-Smad3 interaction in vitro with enhanced solubility. 3) It showed pharmacokinetics suitable for oral qd dosing. 4) No appreciable kinase inhibition was observed when tested against a panel of 30 diverse kinases. Acceptable selectivity profiles were observed with Eurofins Safety 44 and CEREP selectivity panels. 5) Safety profiling did not show any relevant CYP inhibition, hERG, or other cardiac ion channel liabilities. 6) Daily qd dosing of HIPK2i-174 in mouse models of proteinuric CKD significantly reduced proteinuria and renal fibrosis development.
Conclusion
The optimized HIPK2i-174 effectively improved renal function, reduced renal fibrosis development and CKD progression in vivo. Moreover, its enhanced selectivity, bioavailability, and biological activity demonstrate a favorable safety profile in preclinical species for IND-enabling studies.
Funding
- Commercial Support –