Small-Molecule Inhibitors Reveal a New Function for Bcl-2 as a Proangiogenic Signaling Molecule

Zeitlin, Benjamin David

doi:10.1007/82_2010_109

Cited by 9 publications

(12 citation statements)

References 101 publications

(164 reference statements)

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“…Protein-protein interactions are difficult targets for small-molecule ligands (18,(30)(31)(32)(33)(34)(35)(36)(37)(38). The interacting surfaces are large and devoid of structural landmarks, and the interaction energies are typically not focused within a cleft.…”

Section: Discussionmentioning

confidence: 99%

“…These problems are augmented by the bias in available libraries that target enzymes and GPCRs, taking advantage of distinct pockets and grooves that are suitable for highaffinity interactions with small molecules. However, highly effective small-molecule inhibitors of PPI have been identified, and these successes serve as encouraging proofs of principle (18,(31)(32)(33)(34)(38)(39)(40)(41). New strategies for identifying weak binders have become available (42), biophysical and cell-based screening methods are being improved, and different types of libraries are being generated.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitor of MYC identified in a Kröhnke pyridine library

Hart¹,

Garner

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

131

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In a fluorescence polarization screen for the MYC-MAX interaction, we have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Kröhnke pyridine library. The K d of KJ-Pyr-9 for MYC in vitro is 6.5 ± 1.0 nM, as determined by backscattering interferometry; KJ-Pyr-9 also interferes with MYC-MAX complex formation in the cell, as shown in a protein fragment complementation assay. KJ-Pyr-9 specifically inhibits MYC-induced oncogenic transformation in cell culture; it has no or only weak effects on the oncogenic activity of several unrelated oncoproteins. KJ-Pyr-9 preferentially interferes with the proliferation of MYC-overexpressing human and avian cells and specifically reduces the MYC-driven transcriptional signature. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells.M YC is a transcriptional regulator that occupies an apex position in the organizational hierarchy of the cell (1-3). It belongs to a family of basic helix-loop-helix leucine zipper (bHLH-LZ) proteins that dimerize with the small bHLH-LZ protein MAX to become functional (4). The MYC-MAX heterodimer preferentially binds to the palindromic DNA sequence CACGTG, referred to as the E-box motif. As a transcription factor, MYC can bind to the promoters of target genes to stimulate or repress transcriptional activity (5-7). The human genome contains three MYC genes, c-MYC, N-MYC, and L-MYC. Throughout this paper, we will use "MYC" to indicate the protein product of the c-MYC gene.MYC is involved in almost all cancers (8, 9). It is rarely mutated, but achieves gain of function through overexpression or amplification. Because of this broad pathogenic significance, MYC is an important cancer target. However, both conceptual and practical difficulties have stood in the way of identifying potent and effective small-molecule inhibitors of MYC. The conceptual obstacles reflect concern about inhibiting a gene that controls essential cellular activities. Because MYC plays an important role in cell proliferation (10, 11), it is often argued that inhibition of this function would lead to broad and unacceptable side effects in vivo. However, studies with the dominant-negative MYC construct Omomyc have shown that inhibiting MYC has only mild and rapidly reversible effects on normal, fast-proliferating tissues (8,12,13). The main practical difficulty in targeting MYC is the absence of pockets or grooves that could serve as binding sites for small molecules (14).The preferred strategy for the identification of potential MYC inhibitors has been interference with MYC-MAX dimerization (15-18). The formation of the MYC-MAX heterodimer involves the bHLH-LZ domains of the two partner molecules with a protein-protein interaction (PPI) surface of ∼3,200 Å 2 . This surface lacks well-defined binding sites for small molecules and therefore is widely considered as "undruggable." However, despite the large interaction surface, a single-amino acid substitution can completely disrupt the dimerization of MYC with MAX (14...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibitor of MYC identified in a Kröhnke pyridine library

Hart¹,

Garner

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

131

View full text Add to dashboard Cite

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“…All these data support the rational use of apoptosis inducers in combination therapy protocols. Furthermore, it is not surprising that BH3 mimetics such as ABT-737/263 and Bcl-2 antagonists in general also have antiangiogenic properties [111] since Bcl-2 is known to have proangiogenic activities. This may be of value inasmuch as (i) CLL cells constitutively secrete the angiogenic factors VEGF and bFGF and (ii) neo-angiogenesis is an important problem in CLL.…”

Section: Comments and Discussionmentioning

confidence: 99%

Apoptosis inducers in chronic lymphocytic leukemia

Billard

2013

Oncotarget

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Chronic lymphocytic leukemia (CLL) is characterized by a typical defect in apoptosis and is still an incurable disease. Numerous apoptosis inducers have been described. These synthetic compounds and natural products (mainly derived from plants) display antileukemic properties in vitro and in vivo and some have even been tested in the clinic in CLL. They act through several different mechanisms. Most of them involve proteins of the Bcl-2 family, which are the key regulators in triggering the mitochondrial pathway of caspase-dependent apoptosis. Thus, the Mcl-1/Noxa axis appeared as a target. Here I overview natural and synthetic apoptosis inducers and their mechanisms of action in CLL cells. Opportunities for developing novel, apoptosis-based therapeutics are presented.

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“…1C). However, recent work identifies a new function for Bcl-2 in cancer biology that is beyond its classic role in cell survival by its close relationship with VEGF (28, 44). VEGF from paracrine/autocrine of tumor cells and endothelial cells induces expression of Bcl-2 in tumor-associated microvascular endothelial cells (45).…”

Section: Discussionmentioning

confidence: 99%

(−)-Gossypol Suppresses the Growth of Human Prostate Cancer Xenografts via Modulating VEGF Signaling–Mediated Angiogenesis

Pang

Wu²,

Lu³

et al. 2011

Molecular Cancer Therapeutics

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(−)-Gossypol, a natural BH3-mimetic and small-molecule Bcl-2 inhibitor, shows promise in ongoing phase II clinical trials for human cancers. However, whether (−)-gossypol plays functional roles in tumor angiogenesis has not been directly elucidated yet. In this study, we demonstrated that (−)-gossypol dose-dependently inhibited the expression of vascular endothelial growth factor (VEGF), Bcl-2 and Bcl-xL in human prostate cancer cells (PC-3 and DU 145) and human primary cultured umbilical vein endothelial cells (HUVECs) in vitro. Notably, the growth of human prostate tumor PC-3 xenografts in mice was significantly suppressed by (−)-gossypol at dosage of 15 mg/kg/d. This inhibitory action of (−)-gossypol in vivo was largely dependent on suppression of angiogenesis in the solid tumors, where VEGF expression and microvessel density were remarkably decreased. Furthermore, (−)-gossypol inhibited VEGF-induced chemotactic motility and tubulogenesis in HUVECs and human microvascular endothelial cells, and suppressed microvessel sprouting from rat aortic rings ex vivo. When examined for the mechanism, we found that (−)-gossypol blocked the activation of VEGF receptor 2 kinase with the half maximal inhibitory concentration of 2.38 μmol/L in endothelial cells. Consequently, VEGF-triggered phosphorylation of key intracellular proangiogenic molecules, such as Src family kinase, focal adhesion kinase, extracellular signal-related kinase and AKT kinase, were all suppressed by the treatment. Taken together, the present study demonstrates that (−)-gossypol potently inhibits human prostate tumor growth through modulating VEGF signaling pathway, which further validates its great potential in clinical practice.

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Small-Molecule Inhibitors Reveal a New Function for Bcl-2 as a Proangiogenic Signaling Molecule

Cited by 9 publications

References 101 publications

Inhibitor of MYC identified in a Kröhnke pyridine library

Inhibitor of MYC identified in a Kröhnke pyridine library

Apoptosis inducers in chronic lymphocytic leukemia

(−)-Gossypol Suppresses the Growth of Human Prostate Cancer Xenografts via Modulating VEGF Signaling–Mediated Angiogenesis

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