Kidney Week

Abstract: TH-PO0256

Preclinical Evaluation of GENC-231, a Selective NUAK1 Inhibitor, for Kidney Fibrosis

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Cha, Mi Young, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Mi Young Cha, PhD

• Yu, Hyunkyung, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Hyunkyung Yu, PhD

• Kim, Mira, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Mira Kim, PhD

• Park, Kitae, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Kitae Park, DVM

• Jeon, Bunam, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Bunam Jeon, PhD

• Ha, Youngeun, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Youngeun Ha, MS

• Kim, Gyeong-yeon, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Gyeong-yeon Kim, MS

• Kang, Hyeokgu, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Hyeokgu Kang, PhD, RD

• Yoo, Hyunjin, Genome and Company, Suwon-si, Gyeonggi-do, Korea (the Republic of)

Hyunjin Yoo, PhD

Background

Chronic kidney disease drives tubulo-interstitial fibrosis, impairing renal function and leading to end-stage disease. NUAK1 promotes myofibroblast activation and ECM gene expression. Its inhibition offers a novel, mechanism-based strategy to halt fibrotic progression.

Methods

NUAK1 correlations with Banff score and fibrosis markers were analyzed using patient RNA-seq datasets. TGF-β1–induced NUAK1 and α-SMA expression was validated in renal fibroblasts and epithelial cells by RT-PCR and Western blotting. GENC-231 selectivity was profiled across 377 kinases, and IC50 assays confirmed potent and selective NUAK1 inhibition. Anti-fibrotic activity was evaluated in TGF-β1–induced fibrosis models, including marker and gel contraction assays, and in therapeutic mouse models using H&E and Sirius Red staining.

Results

NUAK1, but not NUAK2, was strongly associated with renal fibrosis progression and fibrotic gene signatures. In renal fibroblasts and epithelial cells, NUAK1 and α-SMA expressions increased in a time- and dose-dependent manner upon TGF-β1 stimulation. GENC-231, a selective NUAK1 inhibitor, suppressed TGF-β1-induced fibrotic markers and fibroblast contraction, demonstrating superior efficacy compared with nintedanib and current standards of care. In a fibrosis panel co-culture assay, which more closely mimics the in vivo microenvironment, GENC-231 further modulated fibrotic markers by reducing α-SMA and collagens I/III while increasing MMP-1 and collagen VI. In vivo, GENC-231 demonstrated efficacy in adenine and UUO models, both alone and in combination with dapagliflozin and losartan, resulting in reductions in BUN and creatinine, improvements in fibrosis, and reduced renal injury. Notably, it showed superior efficacy compared with the combination therapy of dapagliflozin and losartan in mouse models.

Conclusion

NUAK1 is a critical driver of renal fibrosis, and inhibition with the selective NUAK1 inhibitor GENC-231 demonstrates strong therapeutic potential. Ongoing preclinical evaluation will advance its development as a novel treatment for renal fibrosis.

Anti-Fibrotic Efficacy of GENC-231 in an Adenine Therapeutic Model

Funding

• Government Support – Non-U.S.