{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T10:03:55Z","timestamp":1763028235987,"version":"3.45.0"},"reference-count":63,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Extracellular glutathione (GSH) is degraded on the cell surface, in which the \u03b3-glutamyl residue is removed to generate cysteine\u2013glycine (Cys\u2013Gly) dipeptides that are subsequently transported to the cytoplasm. Carnosine dipeptidase 2 (CNDP2) is a cytoplasmic enzyme that hydrolyzes Cys\u2013Gly and plays an important role in maintaining intracellular cysteine (Cys) homeostasis. CNDP2-mediated hydrolysis of Cys\u2013Gly promotes Cys mobilization and contributes to the replenishment of intracellular GSH levels. CNDP2 is frequently overexpressed in various cancers and has been implicated in tumor cell proliferation and progression. This mechanism may enhance cancer cell survival by causing resistance to oxidative stress, which indicates that CNDP2 is a potential therapeutic target for cancer treatment. Although bestatin (BES) has been identified as a CNDP2 inhibitor, its limited specificity and suboptimal drug-like properties have limited its therapeutic potential. In this study, we performed an in silico screen of a small-molecule compound library and identified KKL-35 as a novel CNDP2-binding molecule. Molecular dynamics (MD) simulations suggested that KKL-35 interacts within the catalytic pocket. Biochemical assays confirmed that it inhibits CNDP2 enzymatic activity, albeit with lower potency compared with BES. Despite its modest intrinsic activity, KKL-35 exhibits favorable physicochemical and pharmacokinetic properties, which are characterized by a low topological polar surface area (TPSA), reduced molecular flexibility, and well-balanced lipophilicity. This positions it as an attractive and tractable starting point for lead optimization. Taken together, these findings establish KKL-35 as a validated CNDP2 inhibitor and a promising lead compound for the development of more selective therapeutics targeting CNDP2-mediated cancer cell metabolism.<\/jats:p>","DOI":"10.3390\/molecules30224370","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:59:09Z","timestamp":1763027949000},"page":"4370","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of KKL-35 as a Novel Carnosine Dipeptidase 2 (CNDP2) Inhibitor by In Silico Screening"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3886-7411","authenticated-orcid":false,"given":"Takujiro","family":"Homma","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7025-1813","authenticated-orcid":false,"given":"Koki","family":"Shinbara","sequence":"additional","affiliation":[{"name":"Bara Pharma, Tokyo 141-0031, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9487-3253","authenticated-orcid":false,"given":"Tsukasa","family":"Osaki","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14493","DOI":"10.1074\/jbc.M808952200","article-title":"Dug1p Is a Cys-Gly Peptidase of the \u03b3-Glutamyl Cycle of Saccharomyces Cerevisiae and Represents a Novel Family of Cys-Gly Peptidases","volume":"284","author":"Kaur","year":"2009","journal-title":"J. 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