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

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 andr...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Prostate 2024-07, Vol.84 (10), p.909-921
Hauptverfasser: Jasmine, Sumer, Mandl, Adel, Krueger, Timothy E. G., Dalrymple, Susan L., Antony, Lizamma, Dias, Jennifer, Celatka, Cassandra A., Tapper, Amy E., Kleppe, Maria, Kanayama, Mayuko, Jing, Yuezhou, Speranzini, Valentina, Wang, Yuzhuo Z., Luo, Jun, Trock, Bruce J., Denmeade, Samuel R., Carducci, Michael A., Mattevi, Andrea, Rienhoff, Hugh Y., Isaacs, John T., Brennen, W. Nathaniel
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. One Sentence Summary In vitro and in vivo characterization of bomedemstat demonstrates significant target‐specificity for lysine‐specific demethylase 1 over related monoamine oxidase and remarkable safety in preclinical models.
ISSN:0270-4137
1097-0045
1097-0045
DOI:10.1002/pros.24707