Author: Olaoye, Olasunkanmi O. ; Moriggl, Richard ; de Araujo, Elvin D. ; Sedighi, Abootaleb ; Abdallah, Diaaeldin I. ; Hariri, Pearla ; Yu, Wenlong ; Pölöske, Daniel ; Gunning, Patrick T. ; Garcha, Harsimran K.

Herein, we report a potent HDAC6 PROTAC, TO-1187, which selectively degrades HDAC6 in cellulo and demonstrates in vivo efficacy. The design of TO-1187 was achieved by linking our previously reported HDAC6 inhibitor, TO-317, to the cereblon (CRBN) E3 ligase ligand, pomalidomide. TO-1187 achieved monoselective HDAC6 degradation in human multiple myeloma cells, MM.1S, with a D_max of 94% and a DC₅₀ of 5.81 nM after 6 h. Importantly, at concentrations up to 25 μM, TO-1187 exhibited no cellular degradation of other HDACs. Proteomic evaluation confirmed a highly selective proteome-wide degradation profile, with HDAC6 the only protein observed to be depleted. Notably, TO-1187 did not impact the abundance of well-known CRBN neosubstrates, like IKZF1, IKZF3, CK1α, SALL4, and GSPT1. In vivo evaluation confirmed that TO-1187 efficiently degraded HDAC6 in mouse tissues, measured 6 h after intravenous injection. In summary, TO-1187 represents a viable candidate for advanced preclinical evaluation of HDAC6 biology.

11 Mar 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype

Q1 · MEDICINE

Article

Author: Watson, Paris R. ; Cabral, Aaron D. ; Shouksmith, Andrew E. ; Nawar, Nabanita ; Sedighi, Abootaleb ; Abdeldayem, Ayah ; Christianson, David W. ; Hassan, Muhammad Murtaza ; Raouf, Yasir S. ; Israelian, Johan ; de Araujo, Elvin D. ; Manaswiyoungkul, Pimyupa ; Erdogan, Fettah ; Toutah, Krimo ; Geletu, Mulu ; Kachhiyapatel, Niyati ; Radu, Tudor B. ; Olaoye, Olasunkanmi O. ; Gunning, Patrick T. ; Gawel, Justyna M. ; Bukhari, Shazreh

Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure-activity relationship study yielding TO-317, which potently binds HDAC6 catalytic domain 2 (K_i = 0.7 nM) and inhibits the enzyme function (IC₅₀ = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn²⁺ and, uniquely, making a never seen before direct hydrogen bond with the Zn²⁺ coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 Å resolution crystal structure with drHDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors.

100 Deals associated with TO-317

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	Canada	The University of Toronto Mississauga	-
Nervous System Diseases	Preclinical	Canada	The University of Toronto Mississauga	-

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