Experimental antileukemic agents. Preparation and structure-activity study of S-tritylcysteine and related compounds

Zee-Cheng, Kwang-Yuen; Cheng, C. C.

doi:10.1021/jm00297a019

Cited by 27 publications

(29 citation statements)

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“…STLC was a structurally simple lead compound with distinctive antitumor activity [19, 20]. As numerous previous studies had discussed its SAR and co-crystallization structures with Eg5 [40–43], it was clear that STLC analogues were suitable for building our query, and supporting effective screening for novel modulators of the target as well.…”

Section: Discussionmentioning

confidence: 99%

“…In multiple clinical studies, Eg5 inhibitor treatment has shown favorable characteristics such as high tolerance, good pharmacokinetic/pharmacodynamic properties and low CNS toxicity [14, 16–18]. At the same time, other Eg5 inhibitor scaffolds such as S-trityl-L-cysteine (STLC) and its analogues [19, 20], benzimidazoles [21], thioxoimidazolidines [22], phenothiazanes [23], thiophenes [24], and biphenyls [25] are also in development.…”

Section: Introductionmentioning

confidence: 99%

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Eg5 inhibitor YL001 induces mitotic arrest and inhibits tumor proliferation

Wang

et al. 2017

Oncotarget

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Eg5 is a kinesin spindle protein that controls chromosomal segregation in mitosis and is thus a critical drug target for cancer therapy. We report the discovery of a potent, selective inhibitor of Eg5 designated YL001. YL001 was obtained through shape similarity based virtual screening, and it bears a 1,5-disubstituted tetrazole scaffold. YL001 exhibits favorable bioactivity in a variety of cancer cell lines, including taxol-resistant ovarian cancer and 6TG-resistant breast cancer cell lines. This compound inhibits tumor growth by 60% and significantly prolongs median survival time by more than 50% in a xenograft mouse model. YL001 blocks the ATPase activity of Eg5 and causes mitotic failure, ultimately resulting in apoptosis of cancer cells through activation of the caspase-3 pathway. Our findings demonstrate that YL001 is a potent antitumor agent that may be developed for cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Eg5 inhibitor YL001 induces mitotic arrest and inhibits tumor proliferation

Wang

et al. 2017

Oncotarget

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“…STLC was later found to exhibit anti-tumour activity in vivo in murine leukemia models during testing at the National Cancer Institute (NCI) in the 1960s [ 56 ]. It was not until 2004, during the The minimum pharmacophore for inhibition is indicated in black, where: X = S or C; R 1 = NH 2 ; R 2 = H and ≥Pr is present for the third phenyl ring b…”

Section: S -Trityl L-cysteine and Related Inhibitorsmentioning

confidence: 99%

The Discovery and Development of Eg5 Inhibitors for the Clinic

Good

Berretta

Anthony

et al. 2015

Kinesins and Cancer

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“…20 Antitumor activity has been reported for 4 and the p -methoxyphenyl analogue 7 across leukemia, bladder, and prostate xenograft models. 21−23 In initial SAR investigations, analogues with improved cellular potency were identified which incorporated a phenyl containing lipophilic para substituents (e.g., 5 – 7 , Figure 2). 24−26 The subsequent elucidation of the crystal structure of 4 in complex with Eg5 27,28 enabled us to pursue the rational SAR-based optimization of this scaffold, which led to the development of butanamine analogues with improved activity against Eg5 ( 11 – 14 , Figure 2).…”

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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Experimental antileukemic agents. Preparation and structure-activity study of S-tritylcysteine and related compounds

Cited by 27 publications

References 1 publication

Eg5 inhibitor YL001 induces mitotic arrest and inhibits tumor proliferation

Eg5 inhibitor YL001 induces mitotic arrest and inhibits tumor proliferation

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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