{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:01:34Z","timestamp":1788440494906,"version":"build-2803163510"},"posted":{"date-parts":[[2026,6,24]]},"group-title":"Pharmacology and Toxicology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01GM132396"],"award-info":[{"award-number":["R01GM132396"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RSG-21-036-01-TBE"],"award-info":[{"award-number":["RSG-21-036-01-TBE"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Mcl1 is a major driver of therapeutic resistance across hematologic malignancies, but direct Mcl1 inhibition has been limited by on-target cardiotoxicity. Here, building on our development of an Mcl1-targeting autophagy-targeting chimera (AUTAC), we show that AUTAC-mediated degradation creates a tumor-selective therapeutic window that spares the heart. AUTAC induced robust cytotoxicity and Mcl1 degradation in multiple myeloma models, while showing minimal toxicity in cardiac cell lines, primary cardiomyocytes, and murine heart tissue.\n                  <jats:italic>In vivo<\/jats:italic>\n                  , AUTAC reduced tumor Mcl1 without measurably affecting cardiac Mcl1. Mechanistically, this selectivity was associated with lower expression of the p62\/SQSTM1, TRAF6, and UBC13 machinery required for AUTAC activity in cardiac cells, together with lower intracellular AUTAC accumulation relative to tumor cells. AUTAC also enhanced the antitumor activity of carfilzomib and venetoclax, including in resistant models, without worsening cardiotoxicity or promoting cardiac Mcl1 loss. Compared with classical Mcl1 inhibitors, AUTAC caused markedly less cardiomyocyte death, mitochondrial depolarization, and apoptotic signaling. These findings identify AUTAC-mediated Mcl1 degradation as a cardiac-sparing strategy to target an otherwise clinically constrained vulnerability and support tumor-selective lysosomal degradation as a path to safer Mcl1-directed therapy.\n                <\/jats:p>","DOI":"10.64898\/2026.06.18.733247","type":"posted-content","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T23:10:13Z","timestamp":1782342613000},"source":"Crossref","is-referenced-by-count":1,"title":["Tumor-selective Mcl1 degradation by AUTAC uncouples antitumor efficacy from cardiotoxicity"],"prefix":"10.64898","author":[{"given":"Ahmed M.","family":"Elshazly","sequence":"first","affiliation":[{"name":"Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA"},{"name":"Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janakiram R.","family":"Vangala","sequence":"additional","affiliation":[{"name":"Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo G.","family":"Mauro","sequence":"additional","affiliation":[{"name":"Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi N.","family":"Salloum","sequence":"additional","affiliation":[{"name":"Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senthil K.","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA"},{"name":"Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026062704251530000_2026.06.18.733247v1.1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0767"},{"key":"2026062704251530000_2026.06.18.733247v1.2","doi-asserted-by":"crossref","first-page":"699629","DOI":"10.3389\/fphar.2021.699629","article-title":"Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma","volume":"12","year":"2021","journal-title":"Front Pharmacol"},{"key":"2026062704251530000_2026.06.18.733247v1.3","doi-asserted-by":"crossref","first-page":"1436786","DOI":"10.3389\/fphar.2024.1436786","article-title":"KS18, a Mcl-1 inhibitor, improves the effectiveness of bortezomib and overcomes resistance in refractory multiple myeloma by triggering intrinsic apoptosis","volume":"15","year":"2024","journal-title":"Front Pharmacol"},{"key":"2026062704251530000_2026.06.18.733247v1.4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s13045-020-01007-9","article-title":"MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents","volume":"13","year":"2020","journal-title":"Journal of Hematology & Oncology"},{"key":"2026062704251530000_2026.06.18.733247v1.5","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0387"},{"key":"2026062704251530000_2026.06.18.733247v1.6","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1182\/blood.2022017341","article-title":"Mechanisms of resistance to venetoclax","volume":"140","year":"2022","journal-title":"Blood"},{"key":"2026062704251530000_2026.06.18.733247v1.7","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-0028"},{"key":"2026062704251530000_2026.06.18.733247v1.8","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/s41419-021-04240-3","article-title":"A long way to go: caspase inhibitors in clinical use","volume":"12","year":"2021","journal-title":"Cell Death & Disease"},{"key":"2026062704251530000_2026.06.18.733247v1.9","doi-asserted-by":"crossref","unstructured":"Elshazly, A.M. , Hosseini, N. , Vangala, J. , Shen, S. , Neely, V. , Hu, X. , Pagare, P.P. , Harada, H. , Grant, S. , and Radhakrishnan, S.K . 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