Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma

Area of Science:

• Epigenetics
• Oncology
• Pharmacology

Background:

• Lysine-specific demethylase 1 (LSD1) and HDAC6 are epigenetic regulators implicated in various cancers.
• Combined inhibition of LSD1 and HDAC6 presents a promising therapeutic strategy for cancers like multiple myeloma (MM), acute myeloid leukemia (AML), and solid tumors.
• Multiple myeloma (MM) is characterized by a high relapse rate, necessitating the development of novel treatment approaches.

Purpose of the Study:

• To design and develop novel, selective dual inhibitors targeting both LSD1 and HDAC6.
• To evaluate the efficacy and tolerability of these dual inhibitors in preclinical models of multiple myeloma (MM).

Main Methods:

• Design and synthesis of novel dual inhibitors targeting LSD1 and HDAC6.
• In vitro evaluation of compound potency in multiple myeloma (MM) cell lines.
• In vivo efficacy studies using a human MM.1S xenograft mouse model following oral administration.

Main Results:

• The developed dual inhibitor, compound 1, demonstrated superior potency against multiple MM cell lines.
• Compound 1 exhibited superior efficacy compared to single-agent LSD1 or HDAC6 inhibitors in the MM.1S xenograft model.
• Oral administration of compound 1 was well-tolerated in the xenograft model.

Conclusions:

• Novel dual inhibitors targeting LSD1 and HDAC6, such as compound 1, are effective in preclinical models of multiple myeloma (MM).
• Compound 1 represents a promising therapeutic candidate for MM, warranting further investigation.
• The potential of this dual-targeting strategy is being explored for other cancer types.