{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T09:58:30Z","timestamp":1773223110550,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MEXT KAKENHI Grant-in-Aid for Scientific Research","award":["JP23H05473"],"award-info":[{"award-number":["JP23H05473"]}]},{"name":"Grant-in-Aid for Transformative Research Areas","award":["JP23H04882"],"award-info":[{"award-number":["JP23H04882"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Inhibition of histone deacetylase is a highly sought-after objective in the fight against cancer. Thus, the development of innovative HDAC inhibitors with significantly higher potency than SAHA against specific cancer cell types represents complex and demanding work. Method: The utilization of the underexplored and privileged scaffold 4-chlorothieno[2,3-b]pyridine as a cap tethering diverse aliphatic and aromatic linkers, followed by the screening of both cellular and enzymatic activities, is undertaken in this study. Results: Compounds 7a and 9a demonstrated impressive mean GI50 values of 2.15 \u00b5M and 1.89 \u00b5M, respectively. Both compounds reduced caspase-3 levels in RPMI-8226 cells, suggesting induction of apoptosis. Compound 7a showed remarkable IC50 values of 0.37 \u00b5M, 0.58 \u00b5M, and 0.70 \u00b5M against HDACs 1, 4, and 6, respectively, consistent with the cellular assay. Additionally, compound 7a exhibited a selectivity index of 11 for RPMI-8226 cells over PBMCs, reflecting its high selectivity and potential safety. Moreover, ADMET prediction tools indicated that compounds 7a and 9b may have more favorable pharmacokinetic properties than the gold-standard HDAC inhibitor, SAHA. Conclusions: Further study and exploration of the derivatives of compounds 7a and 9a can lead to further advancement in the development of potent HDAC inhibitor anticancer drugs.<\/jats:p>","DOI":"10.3390\/ph19030442","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:16:03Z","timestamp":1773076563000},"page":"442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Harnessing Substituted 4-Chlorothieno[2,3-b]pyridine as a New Cap for Potent and Selective Antiproliferative HDAC Inhibitors"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-1500","authenticated-orcid":false,"given":"Mostafa M.","family":"Badran","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Qena University (Formerly South Valley University), Qena 83523, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9757-2250","authenticated-orcid":false,"given":"Berkay","family":"Beyri","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1225-0720","authenticated-orcid":false,"given":"Hiroshi","family":"Tateishi","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazunori","family":"Shimagaki","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8451-680X","authenticated-orcid":false,"given":"Akiko","family":"Nakata","sequence":"additional","affiliation":[{"name":"Drug Discovery Seeds Development Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0908-8929","authenticated-orcid":false,"given":"Akihiro","family":"Ito","sequence":"additional","affiliation":[{"name":"Drug Discovery Seeds Development Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"},{"name":"Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nao","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9586-2644","authenticated-orcid":false,"given":"Samar H.","family":"Abbas","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt"},{"name":"Medicinal Chemistry Department, Faculty of Pharmacy, Minia National University, New Minia 61768, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Abdel-Aziz","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt"},{"name":"Medicinal Chemistry Department, Faculty of Pharmacy, Minia National University, New Minia 61768, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masami","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"},{"name":"Department of Drug Discovery, Science Farm Ltd., 1-7-30 Kuhonji, Chuo-ku, Kumamoto 862-0976, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4376-5674","authenticated-orcid":false,"given":"Minoru","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Drug Discovery Seeds Development Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan"},{"name":"Office of University Professors, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-4052","authenticated-orcid":false,"given":"Mikako","family":"Fujita","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"},{"name":"Department of Molecular Biology and Genetics, Burdur Mehmet Akif, Ersoy University, Degirmenler Mahallesi-Istiklal Yerleskesi, Yakakoy, Merkez, Burdur 15200, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-3191","authenticated-orcid":false,"given":"Stefan","family":"Br\u00e4se","sequence":"additional","affiliation":[{"name":"Institute of Biological and Chemical Systems\u2014Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaisersrasse 12, 76131 Karlsruhe, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9220-2659","authenticated-orcid":false,"given":"Mohamed O.","family":"Radwan","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"},{"name":"UF Genetics Institute, University of Florida, Gainesville, FL 32610, USA"},{"name":"Department of Cellular and Systems Pharmacology, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"},{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Milazzo, G., Mercatelli, D., Di Muzio, G., Triboli, L., De Rosa, P., 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