Acute myelogenous leukemia (AML) is one of the most common and aggressive forms of acute leukemia affecting 30,000 people per year. Greater than 5 year survival rate still remains around 10-30%, and this depends greatly on the patient's ability to tolerate the combination of cytotoxic chemotherapies, which suppresses much needed haemopoiesis. The limits of current treatment modalities indicate a need for innovative therapies directed against relevant biological targets in AML to improve the clinical outcome. AML is a heterogeneous disease;recent studies have identified a set of activating kinase mutations in FLT-3, c-Kit, and Ras and constitutively active transcription factors such as STAT5 and chimera MLL relevant to disease outcome. One of the major challenges in treating AML is developing therapies that are capable of affecting multiple biological pathways promoting AML proliferation and survival. Histone deacetylase isozyme 6 (HDAC6) is over-expressed in AML patients and is hypothesized to play a key role in maintaining oncogenic signaling through the regulation of heat-shock protein functions that are critical for AML pathogenesis and survival. HDAC6 is also required for malignant cell transformation both in transformed cells and in vivo. Moreover, HDAC6 knock-out mice have been shown to resist mutagen induced tumors and develop normally, which further underscore the potential of HDAC6 as a better tolerated and less toxic therapeutic target for AML. We have identified novel HDAC6-Hsp domain inhibitors, which preferentially inhibit the HDAC6-Hsp deacetylation domain at low ?M concentration and induce Hsp90 acetylation, unlike the canonical hydroxamate HDAC6 inhibitors, tubastatin A and Tubacin. Our overarching hypothesis is that HDAC6-Hsp domain activity promotes AML proliferation and survival by maintaining proper function of multiple heat-shock proteins. Selective HDAC6-Hsp domain inhibition deactivates multiple Hsp activities, attenuates aberrant AML oncogenic signaling, and promotes AML apoptosis. This proposal intends to use multifaceted and innovative approaches to develop novel HDAC6-Hsp domain inhibitors and to investigate the role that HDAC6 plays in the regulation of Hsp activities and apoptosis initiation in AML.
In Aim 1, we will refine our HDAC6-Hsp inhibitors through a phylogenetic library synthesis in order to characterize the structure activity relationship of the HDAC6-Hsp domain.
In Aim 2, we will investigate the HDAC6-Hsp pathway axis, study HDAC6 dependent Hsp70 regulation, and the roles of Hsp70 acetylation play in apoptosome formation. Finally, we will examine our HDAC6-Hsp deacetylation domain inhibitors in vivo using a physiologically relevant disseminated AML xenograft model. We will determine the efficacy of our lead HDAC6 inhibitor candidates against AML, performing pharmacokinetic and dynamic studies on lead inhibitor candidates, and validate the inhibitor's ability to influence biomarkers in vivo.

Public Health Relevance

Acute myelogenous leukemia (AML) is one of the most common and aggressive forms of acute leukemia affecting 30,000 people annually. With an expected increase in American life expectancy, the numbers of AML cases are also expected to increase, as the majority of AML patients are over the age of 60. Little has changed in the standard AML therapies for the last 30 years, and treatments with low cytotoxicity and high therapeutic windows are highly desirable. By studying molecular mechanisms of HDAC6-Hsp domain inhibition and induction of selective AML apoptosis, the development of novel HDAC-Hsp domain inhibitors against AML can be a significant advancement from the current treatment disadvantages.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163452-02
Application #
8628800
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$300,907
Indirect Cost
$99,632
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Li, Xiaoyang; Peterson, Yuri K; Inks, Elizabeth S et al. (2018) Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status. J Med Chem 61:2589-2603
McClure, Jesse J; Inks, Elizabeth S; Zhang, Cheng et al. (2017) Comparison of the Deacylase and Deacetylase Activity of Zinc-Dependent HDACs. ACS Chem Biol 12:1644-1655
Li, Xiaoyang; Zhang, Yingjie; Jiang, Yuqi et al. (2017) Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study. Eur J Med Chem 134:185-206
Gao, Shuai; Zang, Jie; Gao, Qianwen et al. (2017) Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o-phenylenediamine-based zinc binding groups. Bioorg Med Chem 25:2981-2994
Zhang, Cheng; Chou, C James (2016) Metal-Free Direct Amidation of Naphthoquinones Using Hydroxamic Acids as an Amide Source: Application in the Synthesis of an HDAC6 Inhibitor. Org Lett 18:5512-5515
McClure, Jesse J; Zhang, Cheng; Inks, Elizabeth S et al. (2016) Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia. J Med Chem 59:9942-9959
Duan, Wenwen; Li, Jin; Inks, Elizabeth S et al. (2015) Design, synthesis, and antitumor evaluation of novel histone deacetylase inhibitors equipped with a phenylsulfonylfuroxan module as a nitric oxide donor. J Med Chem 58:4325-38
Zhang, Cheng; McClure, Jesse; Chou, C James (2015) Silver-catalyzed direct thiolation of quinones by activation of aryl disulfides to synthesize quinonyl aryl thioethers. J Org Chem 80:4919-27
Li, Xiaoyang; Xu, Wenfang (2014) HDAC1/3 dual selective inhibitors - new therapeutic agents for the potential treatment of cancer. Drug Discov Ther 8:225-8
Rahn, J J; Bestman, J E; Josey, B J et al. (2014) Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy. Neuroscience 259:142-54

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