Characterization of structural, biochemical, pharmacokinetic, and pharmacodynamic properties of the LSD1 inhibitor bomedemstat in preclinical models.

Autor: Jasmine S; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Mandl A; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Krueger TEG; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Dalrymple SL; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Antony L; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Dias J; Imago Biosciences Inc., A Subsidiary of Merck & Co, Inc., San Francisco, California, USA., Celatka CA; Imago Biosciences Inc., A Subsidiary of Merck & Co, Inc., San Francisco, California, USA., Tapper AE; Imago Biosciences Inc., A Subsidiary of Merck & Co, Inc., San Francisco, California, USA., Kleppe M; Imago Biosciences Inc., A Subsidiary of Merck & Co, Inc., San Francisco, California, USA., Kanayama M; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Jing Y; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Speranzini V; Department of Biology and Biotechnology, University of Pavia, Pavia, Italy., Wang YZ; Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.; Department of Experimental Therapeutics, Vancouver Prostate Centre, BC Cancer, Vancouver, British Columbia, Canada., Luo J; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Trock BJ; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Denmeade SR; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Carducci MA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Mattevi A; Department of Biology and Biotechnology, University of Pavia, Pavia, Italy., Rienhoff HY Jr; Imago Biosciences Inc., A Subsidiary of Merck & Co, Inc., San Francisco, California, USA., Isaacs JT; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Brennen WN; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jazyk: angličtina
Zdroj: The Prostate [Prostate] 2024 Jul; Vol. 84 (10), pp. 909-921. Date of Electronic Publication: 2024 Apr 15.
DOI: 10.1002/pros.24707
Abstrakt: Introduction: Lysine-specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis-targeted 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.
Methods: Bomedemstat was characterized via crystallization, flavine adenine dinucleotide spectrophotometry, and enzyme kinetics. On-target 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.
Results: Structural, biochemical, and PK/PD properties of bomedemstat, an irreversible, orally-bioavailable inhibitor of LSD1 are reported. Our data demonstrate bomedemstat has >2500-fold greater specificity for LSD1 over monoamine oxidase (MAO)-A and -B. Bomedemstat also demonstrates activity against several models of advanced CRPC, including NEPC patient-derived xenografts. Significant intra-tumoral accumulation of orally-administered bomedemstat is measured with micromolar levels achieved in vivo (1.2 ± 0.45 µM at the 7.5 mg/kg dose and 3.76 ± 0.43 µM at the 15 mg/kg dose). Daily oral dosing of bomedemstat at 40 mg/kg/day is well-tolerated, with on-target thrombocytopenia observed that is rapidly reversible following treatment cessation.
Conclusions: 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.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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