Rational design of tazarotene

Vasudevan, Jayasree; Chandraratna, Roshantha A.S.

doi:10.1016/j.jaad.2003.10.518

Cited by 1 publication

(1 citation statement)

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“…8 ). The strong inhibitory activity of WYC-209 is unexpected because it is known that after oxidation of the sulfur atom on Tazarotene, the sulfoxide derivative AGN 190844 loses its activity 18 . In addition to its inhibitory effect on growth of B16-F1 TRCs, WYC-209 also completely inhibited the proliferation of unselected B16-F1 melanoma cells cultured on 2D rigid dishes (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of cancer stem cell like cells by a synthetic retinoid

Chen

Cao

et al. 2018

Nat Commun

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Developing novel drugs that can abrogate the growth and metastasis of malignant tumors is a major challenge for cancer researchers. Here we describe a novel synthetic retinoid, namely WYC-209, which inhibits proliferation of malignant murine melanoma tumor-repopulating cells (TRCs), known to resist conventional drug treatment, with an IC50 of 0.19 μM in a dose-dependent manner. WYC-209 also inhibits proliferation of TRCs of human melanoma, lung cancer, ovarian cancer, and breast cancer in culture. Interestingly, the treated TRCs fail to resume growth even after the drug washout. Importantly, the molecule abrogates 87.5% of lung metastases of melanoma TRCs in immune-competent wild-type C57BL/6 mice at 0.22 mg kg−1 without showing apparent toxicity. Pretreating the melanoma TRCs with retinoic acid receptor (RAR) antagonists or with RAR siRNAs blocks or reduces the inhibitory effect of the molecule, suggesting that the target of the molecule is RAR. WYC-209 induces TRC apoptosis and pretreating the TRCs with caspase 3 inhibitor or depleting caspase 3 with siRNAs substantially rescues growth of TRCs from WYC-209 inhibition, suggesting that WYC-209 induces TRCs apoptosis primarily via the caspase 3 pathway. Our findings demonstrate the promise of the new retinoid WYC-209 in treating malignant melanoma tumors with high efficacy and little toxicity.

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Section: Resultsmentioning

confidence: 99%