Lead optimization of HMBA to develop potent HEXIM1 inducers

Zhong, Bo; Lama, Rati; Ketchart, Wannarasmi; Montano, Monica M.; Su, Bin

doi:10.1016/j.bmcl.2014.01.025

Cited by 7 publications

(10 citation statements)

References 17 publications

(15 reference statements)

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“…Our findings have provided unique molecular scaffolds that significantly induced HEXIM1 expression in prostate cancer cells, and have opened a new lead optimization direction for HMBA. We observed increased potency of one of these compounds, 4a1 (Figure 1A), when compared to HMBA in breast cancer MCF7 (Figure 1B), as we have previously observed in prostate cancer cells [24]. 4a1 also induced HEXIM1 expression in other breast cancer cells, MDA-MB-231, MDA-MB-468, and BT474 cells (Figure 1C).…”

Section: Resultssupporting

confidence: 81%

“…We conducted the first study, to the best of our knowledge, that is focused on the lead optimization of HMBA to generate more potent HEXIM1 inducers [24]. Our findings have provided unique molecular scaffolds that significantly induced HEXIM1 expression in prostate cancer cells, and have opened a new lead optimization direction for HMBA.…”

Section: Resultsmentioning

confidence: 99%

“…To further enhance the potential translational impact of our studies, we conducted the first study (to the best of our knowledge) that focused on the lead optimization of HMBA, which resulted in the generation of more potent inducers of HEXIM1 expression such as compound 4a1 [24]. In the reported studies we further tested the therapeutic potential of 4a1.…”

Section: Introductionmentioning

confidence: 99%

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Induction of HEXIM1 activities by HMBA derivative 4a1: Functional consequences and mechanism

et al. 2016

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We have been studying the role of Hexamethylene bisacetamide (HMBA) Induced Protein 1 (HEXIM1) as a tumor suppressor whose expression is decreased in tamoxifen resistant and metastatic breast cancer. HMBA was considered the most potent and specific inducer for HMBA inducible protein 1 (HEXIM1) prior to our studies. Moreover, the ability of HMBA to induce differentiation is advantageous for its therapeutic use when compared to cytotoxic agents. However, HMBA induced HEXIM1 expression required at mM concentrations and induced dose limiting toxicity, thrombocytopenia. Thus we structurally optimized HMBA and identified a more potent inducer of HEXIM1 expression, 4a1. The studies reported herein tested the ability of 4a1 to induce HEXIM1 activities using a combination of biochemical, cell phenotypic, and in vivo assays. 4a1 induced breast cell differentiation, including the stem cell fraction in triple negative breast cancer cells. Clinically relevant HEXIM1 activities that are also induced by 4a1 include enhancement of the inhibitory effects of tamoxifen and inhibition of breast tumor metastasis. We also provide mechanistic basis for the phenotypic effects of 4a1. Our results support the potential of an unsymmetrical HMBA derivative, such as 4a1, as lead compound for further drug development.

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induction of HEXIM1 activities by HMBA derivative 4a1: Functional consequences and mechanism

et al. 2016

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“…2) [18]. The finding provides a unique unsymmetrical molecular scaffold that can induce HEXIM1 expression in prostate and breast cancer cells, and has opened a new lead optimization direction for HMBA [18,19]. Our results support the potential of both symmetrical and unsymmetrical HMBA derivatives as new drug candidates.…”

Section: Introductionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

HMBA is a putative HSP70 activator stimulating HEXIM1 expression that is down-regulated by estrogen

Lama

Gan

Idippily

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is identified as a novel inhibitor of estrogen stimulated breast cell growth, and it suppresses estrogen receptor-α transcriptional activity. HEXIM1 protein level has been found to be downregulated by estrogens. Recently, HEXIM1 has been found to inhibit androgen receptor transcriptional activity as well. Researchers have used Hexamethylene bis-acetamide (HMBA) for decades to stimulate HEXIM1 expression, which also inhibit estrogen stimulated breast cancer cell gene activation and androgen stimulated prostate cancer gene activation. However, the direct molecular targets of HMBA that modulate the induction of HEXIM1 expression in mammalian cells have not been identified. Based on HMBA and its more potent analog 4a1, we designed molecular probes to pull down the binding proteins of these compounds. Via proteomic approach and biological assays, we demonstrate that HMBA and 4a1 are actually heat shock protein 70 (HSP70) binders. The known HSP70 activator showed similar activity as HMBA and 4a1 to induce HEXIM1 expression, suggesting that HMBA and 4a1 might be putative HSP70 activators. Molecular target identification of HMBA and 4a1 could lead to further structural optimization of the parental compound to generate more potent derivatives to stimulate HEXIM1 expression, which could be a novel approach for hormone dependent breast cancer and prostate cancer treatment.

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Combinatorial Chemistry Online Volume 16, Issue 5, May 2014

Terrett

2014

Combinatorial Chemistry - an Online Journal

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Lead optimization of HMBA to develop potent HEXIM1 inducers

Cited by 7 publications

References 17 publications

Induction of HEXIM1 activities by HMBA derivative 4a1: Functional consequences and mechanism

Induction of HEXIM1 activities by HMBA derivative 4a1: Functional consequences and mechanism

HMBA is a putative HSP70 activator stimulating HEXIM1 expression that is down-regulated by estrogen

Combinatorial Chemistry Online Volume 16, Issue 5, May 2014

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