scispace - formally typeset
Open accessJournal ArticleDOI: 10.1073/PNAS.2021847118

Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site.

02 Mar 2021-Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences)-Vol. 118, Iss: 9
Abstract: Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin-GB1 complex.

... read more

Topics: Tubulin (51%)

6 results found

Open accessJournal ArticleDOI: 10.1016/J.JBC.2021.101138
Abstract: Cryptophycin-52 (Cp-52) is potentially the most potent anticancer drug known, with IC50 values in the low picomolar range, but its binding site on tubulin and mechanism of action are unknown. Here, we have determined the binding site of Cp-52, and its parent compound, cryptophycin-1, on HeLa tubulin, to a resolution of 3.3 A and 3.4 A, respectively, by cryo-EM and characterized this binding further by molecular dynamics simulations. The binding site was determined to be located at the tubulin interdimer interface and partially overlap that of maytansine, another cytotoxic tubulin inhibitor. Binding induces curvature both within and between tubulin dimers that is incompatible with the microtubule lattice. Conformational changes occur in both α-tubulin and β-tubulin, particularly in helices H8 and H10, with distinct differences between α and β monomers and between Cp-52-bound and cryptophycin-1-bound tubulin. From these results, we have determined: (i) the mechanism of action of inhibition of both microtubule polymerization and depolymerization, (ii) how the affinity of Cp-52 for tubulin may be enhanced, and (iii) where linkers for targeted delivery can be optimally attached to this molecule.

... read more

Topics: Microtubule polymerization (62%), Microtubule (61%), Tubulin (59%) ... show more

1 Citations

Journal ArticleDOI: 10.1016/J.PHYTOCHEM.2021.112879
14 Jul 2021-Phytochemistry
Abstract: Trikoveramides A – C, members of the kulolide superfamily of cyclic depsipeptides, were isolated from the marine cyanobacterium, Symploca hydnoides, collected from Bintan Island, Indonesia. Their planar structures were elucidated by a combination of NMR spectroscopy and HRMS spectral data. The absolute configurations of the amino acid and phenyllactic acid units were confirmed by Marfey's and chiral HPLC analyses, respectively, while the relative stereochemistry of the 3-hydroxy-2-methyl-7-octynoic acid (Hmoya) unit in trikoveramide A was elucidated by the application of the J-based configuration analysis and NOE correlations. The cytotoxic activity of the trikoveramides were evaluated against MOLT-4 human leukemia cells and gave IC50 values of 9.3 μM, 35.6 μM and 48.8 μM for trikoveramide B, trikoveramide C and trikoveramide A, respectively. In addition, trikoveramides A – C showed weak to moderate inhibition in the quorum sensing inhibitory assay based on the Pseudomonas aeruginosa lasB-gfp and rhlA-gfp bioreporter strains.

... read more

1 Citations

Journal ArticleDOI: 10.1002/CMDC.202100383
06 Oct 2021-ChemMedChem
Abstract: We prepared a series of free NH and N-substituted dibenzonthiazines with potential anti-tumor activity from N-aryl-benzenesulfonamides. A biological test of synthesized compounds (59 samples) was performed in vitro measuring their antiproliferative activity against a panel of six human solid tumor cell lines and its tubulin inhibitory activity. We identified 6-(phenylsulfonyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide and 6-tosyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide as the best compounds with promising values of activity (overall range of 2-5.4 μM). Herein, we report the dibenzothiazine core as a novel building block with antiproliferative activity, targeting tubulin dynamics.

... read more

Topics: Thiazine (54%)

Open accessPosted ContentDOI: 10.1038/S41598-021-01058-Z
03 Nov 2021-Scientific Reports
Abstract: Many agents targeting the colchicine binding site in tubulin have been developed as potential anticancer agents. However, none has successfully made it to the clinic, due mainly to dose limiting toxicities and the emergence of multi-drug resistance. Chalcones targeting tubulin have been proposed as a safe and effective alternative. We have shown previously that quinolone chalcones target tubulin and maintain potent anti-proliferative activity vis-a-vis colchicine, while also having high tolerability and low toxicity in mouse models of cancer and refractivity to multi-drug resistance mechanisms. To identify the most effective anticancer chalcone compound, we synthesized 17 quinolone-chalcone derivatives based on our previously published CTR-17 and CTR-20, and then carried out a structure-activity relationship study. We identified two compounds, CTR-21 [((E)-8-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] and CTR-32 [((E)-3-(3-(2-ethoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] as potential leads, which contain independent moieties that play a significant role in their enhanced activities. At the nM range, CTR-21 and CTR-32 effectively kill a panel of different cancer cells originated from a variety of different tissues including breast and skin. Both compounds also effectively kill multi-drug resistant cancer cells. Most importantly, CTR-21 and CTR-32 show a high degree of selectivity against cancer cells. In silico, both of them dock near the colchicine-binding site with similar energies. Whereas both CTR-21 and CTR-32 effectively prevents tubulin polymerization, leading to the cell cycle arrest at G2/M, CTR-21 has more favorable metabolic properties. Perhaps not surprisingly, the combination of CTR-21 and ABT-737, a Bcl-2 inhibitor, showed synergistic effect in killing cancer cells, since we previously found the "parental" CTR-20 also exhibited synergism. Taken together, CTR-21 can potentially be a highly effective and relatively safe anticancer drug.

... read more

Topics: Chalcone (53%)

Open accessJournal ArticleDOI: 10.3390/CANCERS13225650
Linda Wordeman1, Juan Jesus Vicente1Institutions (1)
12 Nov 2021-Cancers
Abstract: Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies prescribed for cancer treatment. They interfere with microtubule (MT) dynamics by either stabilizing or destabilizing MTs, and in culture, they are believed to kill cells via apoptosis after eliciting mitotic arrest, among other mechanisms. This classical view of MTA therapies persisted for many years. However, the limited success of drugs specifically targeting mitotic proteins, and the slow growing rate of most human tumors forces a reevaluation of the mechanism of action of MTAs. Studies from the last decade suggest that the killing efficiency of MTAs arises from a combination of interphase and mitotic effects. Moreover, MTs have also been implicated in other therapeutically relevant activities, such as decreasing angiogenesis, blocking cell migration, reducing metastasis, and activating innate immunity to promote proinflammatory responses. Two key problems associated with MTA therapy are acquired drug resistance and systemic toxicity. Accordingly, novel and effective MTAs are being designed with an eye toward reducing toxicity without compromising efficacy or promoting resistance. Here, we will review the mechanism of action of MTAs, the signaling pathways they affect, their impact on cancer and other illnesses, and the promising new therapeutic applications of these classic drugs.

... read more


58 results found

Journal ArticleDOI: 10.1038/NRC1187
Gregg L. Semenza1Institutions (1)
Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

... read more

Topics: HIF1A (60%), Hypoxia-inducible factors (56%), Angiogenesis (52%) ... show more

5,551 Citations

Open accessJournal Article
Hua Zhong1, Angelo M. De Marzo, Erik Laughner1, Michael Lim1  +6 moreInstitutions (3)
15 Nov 1999-Cancer Research
Abstract: Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1α subunit. In this study, HIF-1α expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1α was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1α expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1α, whereas benign tumors in breast and uterus did not. HIF-1α overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1α immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1α may play an important role in human cancer progression.

... read more

Topics: Metastasis (62%), Tumor progression (57.99%), Breast cancer (56.99%) ... show more

2,246 Citations

Journal ArticleDOI: 10.1038/NATURE04871
24 May 2006-Nature
Abstract: Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pH(i)) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pH(i)-control systems.

... read more

Topics: Programmed cell death (51%), Cell growth (51%), Cell cycle (50%)

1,472 Citations

Journal ArticleDOI: 10.1038/NATURE02393
11 Mar 2004-Nature
Abstract: Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions. Their dynamic instability is controlled by numerous compounds and proteins, including colchicine and stathmin family proteins. The way in which microtubule instability is regulated at the molecular level has remained elusive, mainly because of the lack of appropriate structural data. Here, we present the structure, at 3.5 A resolution, of tubulin in complex with colchicine and with the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with two tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments shows changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, the tubulin-colchicine complex sheds light on the mechanism of colchicine's activity: we show that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.

... read more

Topics: Tubulin Modulators (71%), Tubulin (64%), Microtubule (62%) ... show more

1,294 Citations

Journal ArticleDOI: 10.1016/S0968-0004(98)01344-9
Chi V. Dang1, Gregg L. Semenza1Institutions (1)
Abstract: Over seven decades ago, classical biochemical studies showed that tumors have altered metabolic profiles and display high rates of glucose uptake and glycolysis. Although these metabolic changes are not the fundamental defects that cause cancer, they might confer a common advantage on many different types of cancers, which allows the cells to survive and invade. Recent molecular studies have revealed that several of the multiple genetic alterations that cause tumor development directly affect glycolysis, the cellular response to hypoxia and the ability of tumor cells to recruit new blood vessels.

... read more

1,050 Citations

No. of citations received by the Paper in previous years
Network Information
Related Papers (5)
Comprehensive Analysis of Binding Sites in Tubulin05 May 2021, Angewandte Chemie

Tobias Mühlethaler, D. Gioia +6 more

78% related
In silico design of tubulin-targeted antimitotic peptides01 Nov 2009, Nature Chemistry

Stefano Pieraccini, Giorgio Saladino +6 more

78% related
Methods in Tubulin Proteomics01 Jan 2010, Methods in Cell Biology

Leah M. Miller, Hui Xiao +4 more

77% related
Fluorescence spectroscopic methods to analyze drug-tubulin interactions.01 Jan 2010, Methods in Cell Biology

Bhabatarak Bhattacharyya, Sonia Kapoor +1 more

75% related
Microtubule targeting agents: from biophysics to proteomics28 Jan 2010, Cellular and Molecular Life Sciences

David Calligaris, Pascal Verdier-Pinard +4 more

75% related