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Discovery of novel 1H-benzo[d]imidazole-4,7-dione based transglutaminase 2 inhibitors as p53 stabilizing anticancer agents in renal cell carcinoma

Authors
 Ga-Ram Kim  ;  Joon Hee Kang  ;  Hyeon Joo Kim  ;  Eunji Im  ;  Jinsu Bae  ;  Woo Sun Kwon  ;  Sun Young Rha  ;  Hyun Cheol Chung  ;  Eun Yi Cho  ;  Soo-Youl Kim  ;  Yong-Chul Kim 
Citation
 BIOORGANIC CHEMISTRY, Vol.143 : 107061, 2024-02 
Journal Title
BIOORGANIC CHEMISTRY
ISSN
 0045-2068 
Issue Date
2024-02
MeSH
Animals ; Antineoplastic Agents* / pharmacology ; Antineoplastic Agents* / therapeutic use ; Carcinoma, Renal Cell* / drug therapy ; Carcinoma, Renal Cell* / pathology ; Cell Line, Tumor ; Humans ; Imidazoles / therapeutic use ; Kidney Neoplasms* / drug therapy ; Kidney Neoplasms* / pathology ; Molecular Docking Simulation ; Protein Glutamine gamma Glutamyltransferase 2* / antagonists & inhibitors ; Transglutaminases / antagonists & inhibitors ; Transglutaminases / metabolism ; Tumor Suppressor Protein p53 / drug effects ; Tumor Suppressor Protein p53 / metabolism
Keywords
Apoptosis ; Renal cell carcinoma ; Transglutaminase 2 ; p53
Abstract
Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure–activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the β-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the β-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC. © 2023 Elsevier Inc.
Full Text
https://www.sciencedirect.com/science/article/pii/S0045206823007228
DOI
10.1016/j.bioorg.2023.107061
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Woo Sun(권우선) ORCID logo https://orcid.org/0000-0003-0268-5624
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/199215
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