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YL143，一种新型的突变选择性不可逆 EGFR 抑制剂，在体外和体内克服了 EGFR 突变耐药性。

YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFR -mutant resistance in vitro and in vivo.

机构信息

School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.

University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.

出版信息

Cancer Med. 2018 Apr;7(4):1430-1439. doi: 10.1002/cam4.1392. Epub 2018 Mar 13.

DOI:10.1002/cam4.1392
PMID:29532998
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5911580/
Abstract

YL143 was identified as a novel wild-type sparing EGFR inhibitor with good pharmacokinetic properties. It potently suppresses EGFR with an 50% inhibitory concentration (IC ) value of 2.0 ± 0.3 nmol/L, but is approximately 92-folds less potent against EGFR kinase. YL143 suppresses cellular proliferation and induces G0/G1 phase arrest and apoptosis in H1975 cells with EGFR mutation at 30 nmol/L. It also exhibits acceptable pharmacokinetics (PK) parameters with an oral bioavailability value of 25.0% after oral administration in rats and exhibits promising antitumor efficacy in a gefitinib-resistant human H1975 xenografted model after oral administration of 30 mg/kg/day. These data supported that YL143 could be a promising lead compound for overcoming clinical EGFR resistance of patients with non-small-cell lung cancer (NSCLC).

摘要

YL143 被鉴定为一种新型的野生型 EGFR 抑制剂，具有良好的药代动力学特性。它能强效抑制 EGFR，其 50%抑制浓度（IC ）值为 2.0±0.3nmol/L，但对 EGFR 激酶的抑制活性约低 92 倍。YL143 能抑制 H1975 细胞的增殖，并在 30nmol/L 浓度下诱导其发生 G0/G1 期阻滞和凋亡，该细胞株存在 EGFR 突变。YL143 在大鼠体内口服生物利用度为 25.0%，药代动力学参数表现可接受，在口服 30mg/kg/day 的剂量下，能在 gefitinib 耐药的人 H1975 异种移植模型中展现出有前景的抗肿瘤疗效。这些数据表明，YL143 可能成为克服非小细胞肺癌（NSCLC）患者临床 EGFR 耐药的有前途的先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/87b7a4833970/CAM4-7-1430-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/c1f21277d9c1/CAM4-7-1430-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/41b60a7a1e29/CAM4-7-1430-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/a65d366c786b/CAM4-7-1430-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/87b7a4833970/CAM4-7-1430-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/c1f21277d9c1/CAM4-7-1430-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/41b60a7a1e29/CAM4-7-1430-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/a65d366c786b/CAM4-7-1430-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a53/5911580/87b7a4833970/CAM4-7-1430-g004.jpg

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本文引用的文献

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Osimertinib improves progression-free survival in NSCLC.奥希替尼可改善非小细胞肺癌的无进展生存期。
Lancet Oncol. 2018 Jan;19(1):e10. doi: 10.1016/S1470-2045(17)30893-8. Epub 2017 Nov 23.
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A novel heterozygous IGF-1 receptor mutation associated with hypoglycemia.一种与低血糖相关的新型杂合型胰岛素样生长因子-1受体突变。
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Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management.与靶向肿瘤治疗相关的高血糖症：机制与管理
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Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer.表皮生长因子受体突变的非小细胞肺癌中的下一代表皮生长因子受体酪氨酸激酶抑制剂
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Management of hyperglycemia from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) targeting T790M-mediated resistance.表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）针对 T790M 介导耐药性的高血糖管理。
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