Discovery of a Hydroxamic Acid-Based HDAC11 Isoform-Selective Inhibitor with Oral Anti-AML Potency

Our previous study not only demonstrated that HDAC11
is a potential
therapeutic target for AML but also discovered a specific HDAC11 inhibitor A9 as an anti-AML lead compound. The purpose of the present
study was to discover novel specific HDAC11 inhibitors with improved
drug-like properties through structural modification and optimization
of A9. Among the newly synthesized A9 derivatives,
compound 25 stood out as a potent and specific HDAC11
inhibitor with desirable liver microsomal stability. Notably, compared
with the well-known HDAC11 inhibitor FT895, compound 25 exhibited much stronger multiple anti-AML effects including proliferation
inhibition, apoptosis induction, cell cycle arrest, differentiation
promotion, and ferroptosis induction. Moreover, combination of 25 and ivosidenib, an approved targeted therapeutic drug for
AML, showed strong synergistic anti-AML potency. Satisfyingly, compound 25 exhibited acceptable oral pharmacokinetic parameters in
mouse, which supported its robust oral anti-AML potency in an MLL-AF9-induced
mouse AML model, both alone and in combination with ivosidenib.