Myosin Modulator Aficamten Inhibits Force by Altering Myosin’s Biochemical Activity Without Changing Thick Filament Structure

Mohran, Saffie, Kooiker, Kristina B., Naim, Ateeqa, Pilagov, Matvey, Asencio, Anthony, Turner, Kyrah L., Ma, Weikang, Flint, Galina, Jiang, Siyao, Zhao, Jing, and others. (2025) Myosin Modulator Aficamten Inhibits Force by Altering Myosin’s Biochemical Activity Without Changing Thick Filament Structure. JACC: Basic to Translational Science, 11 (1). Article Number 101449. ISSN 2452-302X. (doi:10.1016/j.jacbts.2025.101449) (KAR id:112501)

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Official URL: https://doi.org/10.1016/j.jacbts.2025.101449

Abstract

We investigated the effects of aficamten on cardiac muscle structure, biochemical activity, and contractile function. Aficamten does not structurally sequester myosin heads along the thick filament. It inhibits ATPase activity by decreasing myosin ATPase cycling kinetics, with the emergence of a super slow biochemical nucleotide turnover. This results in decreased force and calcium sensitivity without altering cross-bridge cycling. Our myofibril mechanical assay showed inhibition of force with accelerated relaxation. In engineered heart tissues, while mavacamten and aficamten inhibit cardiac twitch forces, mavacamten reduces the activation kinetics while both accelerate relaxation.

Item Type:	Article
DOI/Identification number:	10.1016/j.jacbts.2025.101449
Subjects:	Q Science
Institutional Unit:	Schools > School of Natural Sciences > Biosciences
Former Institutional Unit:	There are no former institutional units.
Funders:	National Institutes of Health (https://ror.org/01cwqze88)
SWORD Depositor:	JISC Publications Router
Depositing User:	Neil Kad
Date Deposited:	21 Jan 2026 15:42 UTC
Last Modified:	23 Jan 2026 16:02 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/112501 (The current URI for this page, for reference purposes)

University of Kent Author Information

Naim, Ateeqa.

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Pilagov, Matvey.

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Kad, Neil M.

Creator's ORCID:	https://orcid.org/0000-0002-3491-8595
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