Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.088
KF-1607, A Novel Pan Src Kinase Inhibitor, Attenuates Obstruction-Induced Tubulointerstitial Fibrosis in Mice
Debra Dorotea1, Seungyeon Lee2, Sun Joo Lee2, Gayoung Lee1, Jung Beom Son2, Hwan Geun Choi2, Sung-Min Ahn3,4,5 and Hunjoo Ha1,*
1Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760,
2New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061,
3Department of Genome Medicine and Science, College of Medicine, Gachon University, Seongnam 13120,
4Department of Hematology-Oncology, Gachon University Gil Hospital, Incheon 21565,
5ImmunoForge, Seoul 08826, Republic of Korea
E-mail: hha@ewha.ac.kr
Tel: +82-2-3277-3001, Fax: +82-2-3277-2851
Received: May 18, 2020; Revised: June 2, 2020; Accepted: June 4, 2020; Published online: July 21, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Src family kinases (SFKs), an important group of non-receptor tyrosine kinases, are suggested to be excessively activated during various types of tissue fibrosis. The present study investigated the effect of KF-1607, an orally active and a newly synthesized Src kinase inhibitor (SKI) with proposed low toxicity, in preventing the progression of renal interstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed in 6-week-old male C57BL/6 mice to induce renal interstitial fibrosis. Either KF-1607 (30 mg/kg, oral gavage) or PP2 (2 mg/kg, intraperitoneal injection), a common experimental SKI, was administered to mice for seven days, started one day prior to surgery. UUO injury induced SFK expression, including Src, Fyn, and Lyn kinase. SFK inhibition by KF-1607 prevented the progression of tubular injury in UUO mice, as indicated by decreases in albuminuria, urinary KIM-1 excretion, and kidney NGAL protein expression. Renal tubulointerstitial fibrosis was attenuated in response to KF-1607, as shown by decreases in α-SMA, collagen I and IV protein expression, along with reduced Masson’s trichrome and collagen-I staining in kidneys. KF-1607 also inhibited inflammation in the UUO kidney, as exhibited by reductions in F4/80 positive-staining and protein expression of p-NFκB and ICAM. Importantly, the observed effects of KF-1607 were similar to those of PP2. A new pan Src kinase inhibitor, KF-1607, is a potential pharmaceutical agent to prevent the progression of renal interstitial fibrosis.
Keywords: Src kinase, Src kinase inhibitor, Ureteral obstruction, Renal fibrosis, Chronic kidney disease


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