Improved Pharmacokinetic Profiles of HDAC6 Inhibitors via Cap Group Modifications

Olasunkanmi O. Olaoye, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Fettah Erdogan, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Maria Gracia-Hernandez, Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, D.C. 20052, United States.
Harsimran Kaur Garcha, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Abootaleb Sedighi, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Qirat F. Ashraf, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Nabanita Nawar, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Mulu Geletu, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Hyuk-Soo Seo, Department of Cancer Biology, Dana Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
Diaaeldin I. Abdallah, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Ayah Abdeldayem, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Muhammad Murtaza Hassan, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Sirano Dhe-Paganon, Department of Cancer Biology, Dana Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
Elvin D. de Araujo, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
Alejandro Villagra, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road NW, Washington, D.C. 20057, United States.
Patrick T. Gunning, Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.

Document Type

Journal Article

Publication Date

8-27-2025

Journal

Journal of medicinal chemistry

DOI

10.1021/acs.jmedchem.5c00479

Abstract

Hydroxamic acid (HA)-based HDAC inhibitors often suffer from poor pharmacokinetic (PK) profiles, limiting their in vivo applications. Cap group modification offers a promising strategy to address these challenges. Here, we optimized the cap group of TO-317, a selective HDAC6 inhibitor with a bisected cap structure, generating 26 analogs with comparable or improved HDAC6 binding affinity and selectivity. Replacing the redundant tetrafluorobenzene sulfonamide cap while retaining the essential picolyl cap group preserved the critical H614 hydrogen bond, as confirmed by X-ray crystallography (1.24-1.27 Å resolution) of five analogs. Analog , featuring a 2-chlorobenzene sulfonamide cap, demonstrated a 120-fold enhancement in plasma concentration in mice compared to that of TO-317. Preclinical studies showed that analog achieved 56% tumor growth inhibition in an SM1 melanoma murine model without observed toxicity. These findings highlight cap group optimization as a powerful approach to enhance HA-based HDAC inhibitors for advanced preclinical and clinical development.

Department

Biochemistry and Molecular Medicine

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