Triphenylbutanamines: Kinesin Spindle Protein Inhibitors with in Vivo Antitumor Activity

Wang, Fang; Good, James A. D.; Rath, Oliver; Kaan, Hung Yi Kristal; Sutcliffe, Oliver B.; Mackay, Simon P.; Kozielski, Frank

doi:10.1021/jm201195m

Cited by 35 publications

(71 citation statements)

References 60 publications

(186 reference statements)

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“…20−23 Recently, they reported new STLC-related compounds, where the sulfur atom in STLC was replaced with CH 2 , and the triphenylbutanamine derivatives showed good oral bioavailability and pharmacokinetics. 24,25 According to their data, the trityl group of STLC was situated in a predominantly hydrophobic core region and was involved in hydrophobic interactions. In particular, the aromaticity and configuration of each phenyl ring in the trityl group are important for interactions such as π−π, CH−π, and edge-to-face interactions with the alkyl side chains of Glu215, Glu116, and Arg119 of KSP, respectively.…”

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Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

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Ishikawa

Sawada

et al. 2015

ACS Med. Chem. Lett.

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Kinesin spindle protein (KSP), known as Hs Eg5, a member of the kinesin-5 family, plays an important role in the formation and maintenance of the bipolar spindle. We previously reported S-trityl-L-cysteine derivatives as selective KSP inhibitors. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of several high affinity derivatives with two fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model in vivo. KEYWORDS: Kinesin spindle protein, L-cysteine derivative, molecular modeling, differential scanning fluorimetry, HCT-116 xenograft model A ntimitotic agents such as microtubule stabilizers (e.g., taxanes) and destabilizers (e.g., vinca alkaloids) have been clinically validated in the treatment of multiple cancers. 1 Eribulin, which is derived from the natural product haricondolyn B, has recently been approved as a microtubule inhibitor with a new mode of action for the treatment of metastatic breast cancer.2 Microtubules play important roles throughout the cell cycle of cancer cells; however, the disruption of microtubule dynamics produces undesirable side effects, such as neurotoxicity and peripheral neuropathy, which are related to the central role tubulin plays in cell signaling and vesicular transport.3 Acquired drug resistance is another obstacle that can arise following long-term use of these agents. 4 To overcome these limitations, novel anticancer agents that do not directly act on microtubules are being developed.5 Kinesin spindle protein (KSP), known as Hs Eg5, a member of the kinesin-5 family, plays an important role in the formation and maintenance of the bipolar spindle.6 Inhibition of KSP leads to cell cycle arrest during mitosis and results in cells with monopolar spindles (so-called monoasters), followed by apoptosis.7 As KSP is absent in postmitotic neurons and is likely to act only in dividing cells, its inhibitors might provide better specificity than microtubule inhibitors in the treatment of human malignancies.8 A large number of KSP inhibitors with various chemical scaffolds have been reported and some of them, including ispinesib (1) and filanesib (known as ARRY-520, 2), have been entered into clinical trials (Figure 1). 9−13Although the clinical efficacy of these inhibitors has been limited to date, better results have recently been obtained in the treatment of hematological malignancies with thiadiazole-based KSP inhibitors, such as filanesib. Currently, filanesib is undergoing clinical evaluation in combination with proteasome inhibitors such as bortezomib or carfilzomib.14 Previously, we reported structure−activity relationship studies (SARs) of S-trityl-L-cysteine (STLC, 3) derivatives as KSP inhibitors (Figure 1). 15 Several STLC derivatives, such as compounds 3a and 3b with a single ...

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Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

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Ishikawa

Sawada

et al. 2015

ACS Med. Chem. Lett.

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“…The primary hydrophilic contribution to binding is from the propylamine, which is oriented towards the bulk solvent and forms a salt bridge with Glu116, thus explaining the preference for a charged moiety in this position. Ispinesib displays reasonable overall drug-like properties, with log D 7.4 = 2.66, moderate aqueous solubility and low clearance in both human microsomes and hepatocytes in vitro [ 21 ]. However, it moderately inhibits hERG (4.81 µM), cytochrome P450 (CYP) 3A4 (4.0 µM), and the P-glycoprotein (Pgp) effl ux pump [ 21 , 22 ].…”

Section: Ispinesibmentioning

confidence: 99%

“…Phenolic derivatives mimicking the hydrogen-bond interaction with Glu218 observed in monastrol also gave improved affi nity (e.g. 6.10 ), but were not pursued due to rapid clearance in hepatocyte assays [ 21 ]. More polar phenyl substituents or a heteroaromatic in place of the solvent exposed phenyl proximal to Tyr211 were introduced to lower log P, but were less successful, and delivered only moderately active inhibitors (e.g.…”

Section: S -Trityl L-cysteine and Related Inhibitorsmentioning

confidence: 99%

“…6.11 ) [ 15 , 21 ]. Replacing the sulfur atom with either O or N yielded weak inhibitors which were ineffective in cell-based assays due to reduced stability, but replacement with CH 2 gave inhibitors with greater potency in cellular assays ( 6.12 ) [ 21 ] and improved GI 50 values across multiple cancer cell lines versus their cysteine counterparts ( 6.13 -6.16 ) [ 15 ].…”

Section: S -Trityl L-cysteine and Related Inhibitorsmentioning

confidence: 99%

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The Discovery and Development of Eg5 Inhibitors for the Clinic

Good

Berretta

Anthony

et al. 2015

Kinesins and Cancer

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“…The crystal structures of Eg5 in complex with 4 , 5 , and 11 have previously been determined and used for structure-based drug design. 26,27,29 …”

Section: Introductionmentioning

confidence: 99%

Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

et al. 2013

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The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-l-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (Kiapp < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

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Triphenylbutanamines: Kinesin Spindle Protein Inhibitors with in Vivo Antitumor Activity

Cited by 35 publications

References 60 publications

Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

The Discovery and Development of Eg5 Inhibitors for the Clinic

Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

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