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Based on the prior serendipitous discovery of the cyclin-dependent kinase 9 (CDK9)-selective PROTAC degrader \u201cTHAL-SNS-032\u201d, developed from the multi-CDK2\/CDK7\/CDK9 inhibitor SNS-032, we speculated that other multi-CDK inhibitors might likewise be transformed into CDK9-selective PROTACs, establishing a \u201clinkerology\u201d platform approach to enhancing CDK family member specificity (and beyond). We tested this hypothesis using AT7519, a multi-CDK2\/CDK5\/CDK9 inhibitor, and employing cereblon as the targeted E3 ligase. Accordingly, we built candidate PROTACs by linking AT7519 to one of two thalidomide derivatives; those molecules in which AT7519 and the thalidomide derivative were coupled via rigid linkers caused greater degradation of the CDK9 protein than those with more flexible linkers. Western blotting of human acute myeloid leukemia (AML) cells treated with AMC-3-221, our most CDK9-selective PROTAC, resulted in almost-complete reduction of the CDK9 protein, with no detectable degradation of CDK1, CDK2, or CDK5, and minimal degradation of CDK4 and CDK6, corroborated by global proteomics analysis. Subtle shortening or lengthening of AMC-3-221\u2019s rigid linker altered the CDK degradation selectivity profile, suggesting that continued linker variation may further enhance selectivity. Molecular modeling provided insight into the observed selectivity through the analyses of ternary complex stabilities. AMC-3-221 treatment rapidly decreased RNA and protein levels of oncogenic downstream targets of CDK9\u2500MCL-1 and c-\/N-MYC\u2500and potently inhibited human AML and other types of human cancer cell lines, with less inhibition of a non-transformed cell line, via an on-target mechanism of apoptosis. AMC-3-221\u2019s CDK9 degradation potency (DC50 &amp;lt; 10 nM) approximated its antileukemic inhibitory potency (IC50 &amp;lt; 50 nM). The maximum tolerated dose in mice of AMC-3-221 was higher than that of another PROTAC, AMC-3-225, consistent with AMC-3-221\u2019s more selective CDK degradation profile. In summary, we demonstrate that converting a multi-CDK inhibitor into a PROTAC with selectivity for CDK9 over other family members is not an isolated phenomenon. Our findings further support the concept that PROTAC linkerology may serve as a platform for enhancing kinase selectivity.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00232","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:34:34Z","timestamp":1788327274000},"page":"2560-2584","source":"Crossref","is-referenced-by-count":0,"title":["Proteolysis Targeting\nChimera (PROTAC) Linkerology\nEnhances the CDK-Degradation Selectivity Profile of a Multi-CDK Inhibitor:\nDiscovery of Potent, Anti-Leukemic CDK9 Degraders"],"prefix":"10.1021","volume":"9","author":[{"given":"Alexandria M.","family":"Chan","sequence":"first","affiliation":[{"name":"University of Maryland School of Pharmacy , , 20 N. Pine Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Eberly","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine , , 20 Penn Street, Room S103 , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Goodis","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , 20 N. Pine Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9139-0152","authenticated-orcid":true,"given":"Erik B.","family":"Nordquist","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , 20 N. Pine Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0008-2732","authenticated-orcid":true,"given":"Mehari","family":"Weldemariam","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , 20 N. Pine Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon A.","family":"Carter-Cooper","sequence":"additional","affiliation":[{"name":"University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center , 22 S. Greene Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Pogash","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , 20 N. Pine Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rena","family":"Lapidus","sequence":"additional","affiliation":[{"name":"University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center , 22 S. Greene Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5525-9170","authenticated-orcid":true,"given":"Maureen A.","family":"Kane","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , 20 N. Pine Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-6804","authenticated-orcid":true,"suffix":"Jr.","given":"Alexander D.","family":"MacKerell","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , 20 N. Pine Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curt I.","family":"Civin","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine , , 20 Penn Street, Room S103 , , ,","place":["Baltimore, Maryland, United States, 21201"]},{"name":"University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center , 22 S. Greene Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4429-8334","authenticated-orcid":true,"given":"Steven","family":"Fletcher","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , 20 N. Pine Street , , ,","place":["Baltimore, Maryland, United States, 21201"]},{"name":"University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center , 22 S. Greene Street , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"2026091109133867800_cit1","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1007\/s11523-025-01169-x","article-title":"MYC as a Target for Cancer Treatment:\nfrom Undruggable to Druggable?","volume":"20","author":"Duffy","year":"2025","journal-title":"Target Oncol."},{"key":"2026091109133867800_cit2","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.bbagrm.2014.03.005","article-title":"Small-molecule inhibitors of the\nMyc oncoprotein","volume":"1849","author":"Fletcher","year":"2015","journal-title":"Biochim. Biophys. 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Cancer\nRes."},{"key":"2026091109133867800_cit18","doi-asserted-by":"publisher","first-page":"678559","DOI":"10.3389\/fonc.2021.678559","article-title":"CDK9: A Comprehensive\nReview of Its Biology, and Its Role as a Potential Target for Anti-Cancer\nAgents","volume":"11","author":"Anshabo","year":"2021","journal-title":"Front. Oncol."},{"key":"2026091109133867800_cit19","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1158\/1535-7163.MCT-18-1023","article-title":"Cyclin-Dependent Kinase-9 Is a Therapeutic Target in\nMYC-Expressing Diffuse Large B-Cell Lymphoma","volume":"18","author":"Hashiguchi","year":"2019","journal-title":"Mol. Cancer Ther."},{"key":"2026091109133867800_cit20","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/gb4184","article-title":"Cyclin-dependent\nkinases","volume":"15","author":"Malumbres","year":"2014","journal-title":"Genome Biol."},{"key":"2026091109133867800_cit21","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nrd.2018.21","article-title":"Kinase\ninhibitors: The road ahead","volume":"17","author":"Ferguson","year":"2018","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026091109133867800_cit22","doi-asserted-by":"publisher","first-page":"15564","DOI":"10.1021\/acs.jmedchem.0c01754","article-title":"Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That\nEnables Short Duration of Target Engagement for the Treatment of Hematological\nMalignancies","volume":"63","author":"Barlaam","year":"2020","journal-title":"J. Med. 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Chem."},{"key":"2026091109133867800_cit25","doi-asserted-by":"publisher","first-page":"4986","DOI":"10.1021\/jm800382h","article-title":"Identification\nof N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide\n(AT7519), a novel cyclin dependent kinase inhibitor using fragment-based\nX-ray crystallography and structure based drug design","volume":"51","author":"Wyatt","year":"2008","journal-title":"J. Med. Chem."},{"key":"2026091109133867800_cit26","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1158\/1535-7163.MCT-08-0890","article-title":"Biological characterization\nof AT7519, a small-molecule inhibitor of cyclin-dependent kinases,\nin human tumor cell lines","volume":"8","author":"Squires","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"2026091109133867800_cit27","unstructured":"National Cancer Institute (NCI).\n          . A Phase\n1 Trial of the Combination\nof the Heat Shock Protein-90 (HSP90) Inhibitor Onalespib (AT13387)\nand the Cyclin-Dependent Kinase (CDK) Inhibitor AT7519M in Patients\nWith Advanced Solid Tumors; Clinical trial registration\nNCT02503709; clinicaltrials.gov, 2022. https:\/\/clinicaltrials.gov\/study\/NCT02503709(October 02, 2025)."},{"key":"2026091109133867800_cit28","unstructured":"NCIC Clinical Trials Group.\n          . A Phase I Study of AT7519M Given\nTwice Weekly in Patients With Advanced Incurable Malignancy; Clinical trial registration NCT00390117; clinicaltrials.gov, 2023. https:\/\/clinicaltrials.gov\/study\/NCT00390117(April 08, 2023)."},{"key":"2026091109133867800_cit29","unstructured":"Astex Pharmaceuticals, Inc.\n          . 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A Phase II Study\nof AT7519M, a CDK\nInhibitor, in Patients With Relapsed and\/or Refractory Chronic Lymphocytic\nLeukemia; Clinical trial registration NCT01627054;\nclinicaltrials.gov, 2023. https:\/\/clinicaltrials.gov\/study\/NCT01627054(April 08, 2023)."},{"key":"2026091109133867800_cit32","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","article-title":"PROTAC targeted protein degraders:\nthe past is prologue","volume":"21","author":"Be\u0301ke\u0301s","year":"2022","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026091109133867800_cit33","doi-asserted-by":"publisher","first-page":"104032","DOI":"10.1016\/j.drudis.2024.104032","article-title":"The impact\nof E3 ligase choice on\nPROTAC effectiveness in protein kinase degradation","volume":"29","author":"Sobierajski","year":"2024","journal-title":"Drug Discovery Today"},{"key":"2026091109133867800_cit34","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1021\/acschembio.2c00804","article-title":"PROTAC Linkerology\nLeads to an Optimized\nBivalent Chemical Degrader of Polycomb Repressive Complex 2 (PRC2)\nComponents","volume":"18","author":"Bashore","year":"2023","journal-title":"ACS Chem. Biol."},{"key":"2026091109133867800_cit35","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.chembiol.2017.09.010","article-title":"Lessons in PROTAC Design from Selective\nDegradation with a Promiscuous Warhead","volume":"25","author":"Bondeson","year":"2018","journal-title":"Cell\nChem. 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Chem."},{"key":"2026091109133867800_cit38","unstructured":"https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast(May 1, 2026)."},{"key":"2026091109133867800_cit39","doi-asserted-by":"publisher","first-page":"4637","DOI":"10.1182\/blood-2008-12-190256","article-title":"Mechanism of action\nof SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic\nlymphocytic leukemia","volume":"113","author":"Chen","year":"2009","journal-title":"Blood"},{"key":"2026091109133867800_cit40","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/nchembio.2538","article-title":"Pharmacological perturbation of CDK9 using selective\nCDK9 inhibition or degradation","volume":"14","author":"Olson","year":"2018","journal-title":"Nat. Chem. Biol."},{"key":"2026091109133867800_cit41","doi-asserted-by":"publisher","first-page":"115342","DOI":"10.1016\/j.ejmech.2023.115342","article-title":"Bifunctional\ndegraders of cyclin dependent kinase 9 (CDK9): Probing the relationship\nbetween linker length, properties, and selective protein degradation","volume":"254","author":"Tokarski","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"2026091109133867800_cit42","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.1021\/acs.jmedchem.4c01621","article-title":"Identification of a\nPotent and Selective CDK9 Degrader as a Targeted Therapeutic Option\nfor the Treatment of Small-Cell Lung Cancer","volume":"68","author":"Wang","year":"2025","journal-title":"J. Med. 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