Tubulin Colchicine Binding Site Inhibitors as Vascular Disrupting Agents in Clinical Developments

Ji, Ya-Ting; Liu, Yanna; Liu, Zhaopeng

doi:10.2174/0929867322666150114163732

Cited by 89 publications

(91 citation statements)

References 64 publications

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“…As inhibitors of tubulin assembly, these compounds were compared with combretastatin A-4 (CA, figure 8), the active metabolite of the water soluble prodrug combretastatin A-4 phosphate (Zybrestat, Fosbretabulin), which has orphan drug status for ovarian cancer. 47 Compounds 5, 7 and 8 were effective and potent inhibitors of bovine tubulin assembly, with activity comparable to that of CA. Compound 5 , the conformationally restricted tetrahydroquinoline analog of 3 , was almost 7-fold more potent than 3 .…”

Section: Biological Evaluations and Discussionmentioning

confidence: 94%

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

Pavana

Choudhary

Bastian

et al. 2017

Bioorganic & Medicinal Chemistry

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The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI50 values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin.

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Section: Biological Evaluations and Discussionmentioning

confidence: 94%

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

Pavana

Choudhary

Bastian

et al. 2017

Bioorganic & Medicinal Chemistry

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“…Several clinically relevant VDAs including CA4P , 41–45 CA1P , 43,46 BNC105 , 15,16,43,45,47 AVE8062 , 43,48–50 and ZD6126 . 42,43,51 …”

Section: Figurementioning

confidence: 99%

Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization

et al. 2016

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The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50 < 5 μM), and benzocyclooctene phenol 23 was comparable to KGP18 in terms of potency. The analogous indene-based compound 31 also functioned as an inhibitor of tubulin polymerization (IC50 = 11 μM) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue 23, and it was converted to its water-soluble prodrug salt 24 to assess its potential as a VDA. Preliminary in vivo studies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with 24 (120 mg/kg) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies with CA4P, a clinically relevant VDA, were carried out as a positive control.

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“…First, drugs binding to the colchicine binding pocket may overcome mechanisms of drug resistance, which will be discussed herein. Also, colchicine binding site inhibitors can target tumor vasculature and prevent the formation of new blood vessels or disrupt existing microvessels . For these reasons, the colchicine binding site is an attractive target for the development of chemotherapeutic drugs and numerous scaffolds are being investigated.…”

Section: Introductionmentioning

confidence: 99%

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

Medicinal Research Reviews

122

107

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Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

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Tubulin Colchicine Binding Site Inhibitors as Vascular Disrupting Agents in Clinical Developments

Cited by 89 publications

References 64 publications

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

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