The small organic compound HMN-176 delays satisfaction of the spindle assembly checkpoint by inhibiting centrosome-dependent microtubule nucleation

DiMaio, Michael A.; Mikhailov, Alexei; Rieder, Conly L.; Hoff, Daniel D. Von; Palazzo, Robert E.

doi:10.1158/1535-7163.mct-08-0876

Cited by 11 publications

(7 citation statements)

References 32 publications

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“…Replacement of the ABT‐751 amino spacer ( SM4 ) with an ethylene gives stilbene‐sulfonamides, mitotic arrest inducers with mechanisms different from tubulin binding (Figure bottom right) . HMN‐214 is a prodrug that produces the active metabolite HMN‐176 by carboxylesterases hydrolysis .…”

Section: The Sulfonamidesmentioning

confidence: 99%

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Vicente‐Blázquez

González

Álvarez

et al. 2018

Medicinal Research Reviews

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Tubulin, the microtubules and their dynamic behavior are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal drug targets. Sulfonamides are exemplary drugs with applications in the clinic, in veterinary and in the agrochemical industry. This review summarizes the actual state and recent progress of both fields looking from the double point of view of the target and its drugs, with special focus onto the structural aspects. The article starts with a brief description of tubulin structure and its dynamic assembly and disassembly into microtubules and other polymers. Posttranslational modifications and the many cellular means of regulating and modulating tubulin's biology are briefly presented in the tubulin code. Next, the structurally characterized drug binding sites, their occupying drugs and the effects they induce are described, emphasizing on the structural requirements for high potency, selectivity, and low toxicity. The second part starts with a summary of the favorable and highly tunable combination of physical-chemical and biological properties that render sulfonamides a prototypical example of privileged scaffolds with representatives in many therapeutic areas. A complete description of tubulin-binding sulfonamides is provided, covering the different species and drug sites. Some of the antimitotic sulfonamides have met with very successful Med Res Rev. 2019;39:775-830. wileyonlinelibrary.com/journal/med © 2018 Wiley Periodicals, Inc. | 775applications and others less so, thus illustrating the advances, limitations, and future perspectives of the field.All of them combine in a mechanism of action and a clinical outcome that conform efficient drugs. K E Y W O R D S molecular mechanisms, sulfonamides, tubulin binding drugs, tubulin binding sites 1 | INTRODUCTION Drugs targeting tubulin and the microtubules (tubulin binding drugs [TBDs]) are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal agents with applications in the clinic, in veterinary and in the agrochemical industry. Recently, the combination of computational methods, medicinal chemistry, biochemistry, structural biology, and cell biology is starting to unravel the intricacies of tubulin binding drugs and of the microtubules themselves, thus paving the way towards new and better TBDs. New methodological advances such as the high resolution cryo-electron microscopy, the imaging of individual microtubule dynamics, and the achievement of recombinant tubulin, altogether with more established methodologies for the study of the microtubules have combined to provide a sharper view of the structure and function of these essential cell components and their interactions with clinically important drugs. The sulfonamides are a prototypical example of privileged scaffolds, with representatives in many therapeutic areas, due to a combination of favorable and highly tunable physical-chemical and biological properties. The early discovery of the dinitroaniline herbicides, and mainly the seminal discovery o...

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Section: The Sulfonamidesmentioning

confidence: 99%

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Vicente‐Blázquez

González

Álvarez

et al. 2018

Medicinal Research Reviews

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“…This stilbene derivative is an active form of an oral prodrug, HMN-214. HMN-176 disrupts mitotic spindle assembly, inhibits centrosome-dependent microtubule nucleation, and is considered an "anticentrosome" agent (48). It does not directly inhibit the enzymatic activity of Plk1 but rather affects subcellular distribution of Plk1 (49).…”

Section: Inhibitors Targeting the Polo Box Domain Of Plk1mentioning

confidence: 99%

Polo-like Kinase 1 Inhibitors and Their Potential Role in Anticancer Therapy, with a Focus on NSCLC

Medema

Lin

Yang

2011

Clinical Cancer Research

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Cytotoxic platinum-doublet chemotherapy that includes antimitotic agents is a current standard of care in advanced non-small cell lung cancer (NSCLC). Microtubule-targeting antimitotics, taxanes, and Vinca alkaloids are effective anticancer therapeutics that affect both dividing and nondividing cells. A new generation of antimitotic agents that target regulatory proteins-mitotic kinases and kinesins-has the potential to overcome the limitations related to the role of tubulin in nondividing cells that are associated with traditional antimitotics. This review concentrates on Polo-like kinase 1, a key regulator of mitosis, outlines a rationale for its development as an anticancer target, and discusses data from preclinical and clinical studies of Plk1 inhibitors with a particular focus on NSCLC. Clin Cancer Res; 17(20); 6459-66. Ó2011 AACR. Current Treatment OptionsLung cancer is the second most common malignancy in the United States (219,440 cases) and was the leading cause of cancer-related mortality (159,390 deaths) in 2009 (1). Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers (2); approximately 40% are diagnosed with advanced or metastatic disease (3) with a 5-year survival rate of 14% (4).Chemotherapy with platinum-based doublets (e.g. paclitaxel/carboplatin, docetaxel/cisplatin, gemcitabine/cisplatin, and pemetrexed/cisplatin) is the standard of care in first-line treatment of advanced NSCLC with median overall survival of approximately 8 months (5) and overall response rate of 19% to 30% (5, 6

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“…While studies on the pharmacological properties of natural and synthetic stilbene derivatives are numerous, 22 reports related to their heterocyclic aza analogues are comparatively scarce. Representatives of this class of compounds have been found to display protein kinase inhibitory, 23 anti-inflammatory 24 and antiproliferative 25 activities, as well as other various biological properties. 26 The structures of the synthetic nitrogen-containing stilbene derivatives which are the subject of this work are depicted in Fig.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of cytotoxic nitrogen-containing heterocyclic stilbene analogues on VEGF protein secretion and VEGF, hTERT and c-Myc gene expression

et al. 2015

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The small organic compound HMN-176 delays satisfaction of the spindle assembly checkpoint by inhibiting centrosome-dependent microtubule nucleation

Cited by 11 publications

References 32 publications

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Polo-like Kinase 1 Inhibitors and Their Potential Role in Anticancer Therapy, with a Focus on NSCLC

Inhibitory effect of cytotoxic nitrogen-containing heterocyclic stilbene analogues on VEGF protein secretion and VEGF, hTERT and c-Myc gene expression

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