Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia

Andrew E. Shouksmith; Justyna M. Gawel; Nabanita Nawar; Diana Sina; Yasir S. Raouf; Shazreh Bukhari; Liying He; Alexandra E. Johns; Pimyupa Manaswiyoungkul; Olasunkanmi O. Olaoye; Aaron D. Cabral; Abootaleb Sedighi; Elvin D. De Araujo; Patrick T. Gunning

doi:10.1021/acsmedchemlett.9b00471

Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia

Andrew E. Shouksmith, Justyna M. Gawel, Nabanita Nawar, Diana Sina, Yasir S. Raouf, Shazreh Bukhari, Liying He, Alexandra E. Johns, Pimyupa Manaswiyoungkul, Olasunkanmi O. Olaoye, Aaron D. Cabral, Abootaleb Sedighi, Elvin D. De Araujo, Patrick T. Gunning

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

Abstract

The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound 51 also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that 51 dose-dependently triggers apoptosis in AML cells through HDAC inhibition.

Original language	English
Pages (from-to)	56-64
Number of pages	9
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	1
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00471
Publication status	Published - Jan 9 2020
Externally published	Yes

Keywords

acute myeloid leukemia
enzyme inhibition
histone deacetylases
pharmacokinetics

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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Shouksmith, A. E., Gawel, J. M., Nawar, N., Sina, D., Raouf, Y. S., Bukhari, S., He, L., Johns, A. E., Manaswiyoungkul, P., Olaoye, O. O., Cabral, A. D., Sedighi, A., De Araujo, E. D., & Gunning, P. T. (2020). Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia. ACS Medicinal Chemistry Letters, 11(1), 56-64. https://doi.org/10.1021/acsmedchemlett.9b00471

Shouksmith, AE, Gawel, JM, Nawar, N, Sina, D, Raouf, YS, Bukhari, S, He, L, Johns, AE, Manaswiyoungkul, P, Olaoye, OO, Cabral, AD, Sedighi, A, De Araujo, ED & Gunning, PT 2020, 'Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia', ACS Medicinal Chemistry Letters, vol. 11, no. 1, pp. 56-64. https://doi.org/10.1021/acsmedchemlett.9b00471

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abstract = "The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound 51 also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that 51 dose-dependently triggers apoptosis in AML cells through HDAC inhibition.",

keywords = "acute myeloid leukemia, enzyme inhibition, histone deacetylases, pharmacokinetics",

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AU - Sina, Diana

AU - Raouf, Yasir S.

AU - Bukhari, Shazreh

AU - He, Liying

AU - Johns, Alexandra E.

AU - Manaswiyoungkul, Pimyupa

AU - Olaoye, Olasunkanmi O.

AU - Cabral, Aaron D.

AU - Sedighi, Abootaleb

AU - De Araujo, Elvin D.

AU - Gunning, Patrick T.

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Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia

Abstract

Keywords

ASJC Scopus subject areas

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