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DualPG\u2010DTA is presented, a general framework for binding affinity prediction that integrates two pre\u2010trained language models to generate atomic\u2010level molecular representations and residue\u2010level protein embeddings. The architecture constructs dual molecular\u2010protein graphs processed through dedicated graph neural networks equipped with dynamic attention mechanisms to extract context\u2010aware sequence\u2010level features, which are fused via a multimodal module for affinity predictions. Benchmark results show that DualPG\u2010DTA consistently outperforms existing models across all metrics. Applied to CDK9 inhibitor discovery, the framework is used to develop robust regression\/classification models and identified compound\n                    <jats:bold>C1<\/jats:bold>\n                    as a novel CDK9 inhibitor with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 1.2 nM.\n                    <jats:bold>C1<\/jats:bold>\n                    demonstrates exceptional CDK family selectivity alongside optimal pharmacokinetic properties, including prolonged half\u2010life, adequate clearance, robust plasma exposure, and oral bioavailability. Notably, oral\n                    <jats:bold>C1<\/jats:bold>\n                    demonstrated potent antitumor efficacy in a Venetoclax\u2010resistant MV4\u201011 acute myeloid leukemia (AML) xenograft model, with concurrent demonstration of favorable tolerability and safety profiles. Collectively, the study not only establishes a unified framework for precise binding affinity prediction but also identifies\n                    <jats:bold>C1<\/jats:bold>\n                    as a highly promising therapeutic lead targeting CDK9 to conquer Venetoclax resistance in AML.\n                  <\/jats:p>","DOI":"10.1002\/advs.202513099","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T12:03:47Z","timestamp":1769515427000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["DualPG\u2010DTA: A Large Language Model\u2010Powered Graph Neural Network Framework for Enhanced Drug\u2010Target Affinity Prediction and Discovery of Novel CDK9 Inhibitors Exhibiting In Vivo Anti\u2010Leukemia Activity"],"prefix":"10.1002","volume":"13","author":[{"given":"Yihao","family":"Chen","sequence":"first","affiliation":[{"name":"Joint International Research Laboratory of Synthetic Biology and Medicine Ministry of Education Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals School of Biology and Biological Engineering South China University of Technology  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jindi","family":"Huang","sequence":"additional","affiliation":[{"name":"Joint International Research Laboratory of Synthetic Biology and Medicine Ministry of Education Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals School of Biology and Biological Engineering South China University of Technology  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment School of Pharmacy Jinan University  Guangzhou 510632 China"},{"name":"International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education Guangzhou City Key Laboratory of Precision Chemical Drug Development School of Pharmacy Jinan University  Guangzhou 510632 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shipeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Joint International Research Laboratory of Synthetic Biology and Medicine Ministry of Education Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals School of Biology and Biological Engineering South China University of Technology  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinze","family":"Li","sequence":"additional","affiliation":[{"name":"Joint International Research Laboratory of Synthetic Biology and Medicine Ministry of Education Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals School of Biology and Biological Engineering South China University of Technology  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment School of Pharmacy Jinan University  Guangzhou 510632 China"},{"name":"International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education Guangzhou City Key Laboratory of Precision Chemical Drug Development School of Pharmacy Jinan University  Guangzhou 510632 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tie\u2010Gen","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery Shanghai Institute of Materia Medica Chinese Academy of Sciences  Zhongshan 528400 China"},{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5116-7749","authenticated-orcid":false,"given":"Ling","family":"Wang","sequence":"additional","affiliation":[{"name":"Joint International Research Laboratory of Synthetic Biology and Medicine Ministry of Education Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals School of Biology and Biological Engineering South China University of Technology  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1109\/TCBB.2020.3046945"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty593"},{"key":"e_1_2_8_3_1","author":"\u00d6zt\u00fcrk H.","year":"2019","journal-title":"arXiv"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1109\/TCBB.2022.3170365"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaa921"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c00866"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiolchem.2023.107971"},{"key":"e_1_2_8_8_1","author":"Devlin J.","year":"2018","journal-title":"arXiv"},{"key":"e_1_2_8_9_1","first-page":"1877","volume":"33","author":"Brown T.","year":"2020","journal-title":"Adv. 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