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Unfortunately, drug resistance is making the treatment of B-cell malignancies challenging. In this study, we employed a dual machine learning drug design approach that involves two parallel branches: the QSAR-GFA modeling (Branch 1) which engages the development of an interpretable structure activity relationships, and the KNIME\u00ae based machine learning modeling (Branch 2) which aimed at achieving high predictive accuracy. Subsequently, six machine learning modules, encompassing; the Random Forest model, the XGBoost Model (XGBoost), the Naive Bayes model, the k-Nearest Neighbors model, and the Support Vector Machines model were applied. Later, experimental validation through cytotoxicity assays against Raji lymphoma and K562 leukemia cell lines revealed several compounds that are exhibiting notable biological activity. For instance, compounds 166 and 168 which are acridine based displayed IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 0.087 and 4.92\u00a0\u00b5M in Raji cells, respectively. Also, hits 166 and 168 were subjected to enzymatic evaluation by using a radiometric HotSpot\u2122 kinase assay against BTK and yielded an IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 12.2\u00a0\u00b5M and 23.8\u00a0\u00b5M, respectively. Finally, a key outcome of this study is the identification of a chemically distinct and novel, acridine-based antiproliferative hit candidates with measurable BTK inhibitory activity.\n                  <\/jats:p>","DOI":"10.1007\/s10822-026-00912-4","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T07:10:39Z","timestamp":1788246639000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of novel acridine based inhibitors of Bruton\u2019s tyrosine kinase (BTK) via pharmacophore modeling and machine learning-driven virtual screening followed by molecular dynamic studies"],"prefix":"10.1007","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7330-4433","authenticated-orcid":false,"given":"Rand","family":"Shahin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sawsan","family":"Jaafreh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Mansi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rufaida","family":"Al Zoubi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bashaer","family":"Abu-Irmaileh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3562-6963","authenticated-orcid":false,"given":"Yusra","family":"Azzam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Azzam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"912_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11206139","author":"N Garg","year":"2022","unstructured":"Garg N, Padron EJ, Rammohan KW, Goodman CF (2022) Bruton\u2019s tyrosine kinase inhibitors: the next frontier of B-cell-targeted therapies for cancer, autoimmune disorders, and multiple sclerosis. 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