{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T22:11:11Z","timestamp":1786831871790,"version":"build-2736575974"},"reference-count":30,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004437","name":"European Association for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004437","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Lysine\u2010specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration\u2010resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis\u2010targeted therapies. Safe and effective LSD1 inhibitors are necessary to determine antitumor response in prostate cancer models. For this reason, we characterize the LSD1 inhibitor bomedemstat to assess its clinical potential in NEPC as well as other mCRPC pathological subtypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Bomedemstat was characterized via crystallization, flavine adenine dinucleotide spectrophotometry, and enzyme kinetics. On\u2010target effects were assessed in relevant prostate cancer cell models by measuring proliferation and H3K4 methylation using western blot analysis. In vivo, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of bomedemstat are also described.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Structural, biochemical, and PK\/PD properties of bomedemstat, an irreversible, orally\u2010bioavailable inhibitor of LSD1 are reported. Our data demonstrate bomedemstat has &gt;2500\u2010fold greater specificity for LSD1 over monoamine oxidase (MAO)\u2010A and \u2010B. Bomedemstat also demonstrates activity against several models of advanced CRPC, including NEPC patient\u2010derived xenografts. Significant intra\u2010tumoral accumulation of orally\u2010administered bomedemstat is measured with micromolar levels achieved in vivo (1.2\u2009\u00b1\u20090.45\u2009\u00b5M at the 7.5\u2009mg\/kg dose and 3.76\u2009\u00b1\u20090.43\u2009\u00b5M at the 15\u2009mg\/kg dose). Daily oral dosing of bomedemstat at 40\u2009mg\/kg\/day is well\u2010tolerated, with on\u2010target thrombocytopenia observed that is rapidly reversible following treatment cessation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Bomedemstat provides enhanced specificity against LSD1, as revealed by structural and biochemical data. PK\/PD data display an overall safety profile with manageable side effects resulting from LSD1 inhibition using bomedemstat in preclinical models. Altogether, our results support clinical testing of bomedemstat in the setting of mCRPC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.24707","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T10:22:13Z","timestamp":1713176533000},"page":"909-921","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Characterization of structural, biochemical, pharmacokinetic, and pharmacodynamic properties of the LSD1 inhibitor bomedemstat in preclinical models"],"prefix":"10.1002","volume":"84","author":[{"given":"Sumer","family":"Jasmine","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel","family":"Mandl","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC) Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E. G.","family":"Krueger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Dalrymple","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC) Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizamma","family":"Antony","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC) Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Dias","sequence":"additional","affiliation":[{"name":"Imago Biosciences Inc., A Subsidiary of Merck &amp; Co, Inc. San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra A.","family":"Celatka","sequence":"additional","affiliation":[{"name":"Imago Biosciences Inc., A Subsidiary of Merck &amp; Co, Inc. San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Tapper","sequence":"additional","affiliation":[{"name":"Imago Biosciences Inc., A Subsidiary of Merck &amp; Co, Inc. San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kleppe","sequence":"additional","affiliation":[{"name":"Imago Biosciences Inc., A Subsidiary of Merck &amp; Co, Inc. San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuko","family":"Kanayama","sequence":"additional","affiliation":[{"name":"Department of Urology, James Buchanan Brady Urological Institute Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuezhou","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Urology, James Buchanan Brady Urological Institute Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Speranzini","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology University of Pavia Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-8591","authenticated-orcid":false,"given":"Yuzhuo Z.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urologic Sciences Vancouver Prostate Centre, University of British Columbia Vancouver British Columbia Canada"},{"name":"Department of Experimental Therapeutics Vancouver Prostate Centre, BC Cancer Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC) Johns Hopkins University School of Medicine Baltimore Maryland USA"},{"name":"Department of Urology, James Buchanan Brady Urological Institute Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce J.","family":"Trock","sequence":"additional","affiliation":[{"name":"Department of Urology, James Buchanan Brady Urological Institute Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5442-515X","authenticated-orcid":false,"given":"Samuel R.","family":"Denmeade","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC) Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Carducci","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC) Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mattevi","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology University of Pavia Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Hugh Y.","family":"Rienhoff","sequence":"additional","affiliation":[{"name":"Imago Biosciences Inc., A Subsidiary of Merck &amp; Co, Inc. 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