每周分子 | Molecule of the Week
Molecule of the Week: Larotrectinib
每周分子：拉罗替尼
拉罗替尼(商品名Vitrakvi)是Array BioPharma公司(科罗拉多州博尔德市)在21世纪发现的一种抗癌药物。2013年，Array将其许可给了Loxo Oncology公司(康涅狄格州斯坦福，加利福尼亚州南旧金山)。这款药物由Loxo(现在是礼来公司印第安纳波利斯]的一部分)和拜耳公司(德国勒沃库森)联合开发。2018年，美国食品药品监督管理局批准了拉罗替尼用于治疗具有某种遗传标记的癌症患者。
拉罗替尼是继默克公司Keytruda之后被FDA批准的第二款“组织不可知”药物(第一个小分子药物)。“组织不可知”意味着这款药物不是针对特定器官的癌症，而是针对由特定基因突变引起的癌症。
一种基因突变产生的肿瘤是原肌球蛋白激酶(TRK)家族中的酶融合的结果。拉罗替尼抑制TRK融合，并缩小多种癌症产生的肿瘤。
一如既往，此处有隐情。Vitrakvi贵得离谱。Loxo-Bayer合营公司将Vitrakvi药丸的每月批发采购成本定为32,800美元。液体处方的价格(主要为儿童用药)略低，为11,000美元。由于TRK融合突变患者的罕见性，这些公司认为其定价是合理的。
拉罗替尼信息速览
| CAS登记号 | 1223403-58-4 |
| 分子式 | C21H22F2N6O2 |
| 摩尔质量 | 428.44 g/mol |
| 外观 | 黄色粉末 |
| 熔点 | 未提供 |
| 水溶性 | 不溶 |
拉罗替尼危害信息
| GHS 分类*: 皮肤刺激，分类2 | |
| H315—皮肤刺激 | |
| GHS 分类：皮肤刺激，分类1 | |
| H317—可致皮肤过敏反应 | |
| GHS 严重的眼损伤/眼刺激，分类1 | |
| H318—可致严重的眼损伤 | |
| GHS 分类：呼吸致敏，分类1 | |
| H334—吸入可致过敏或哮喘症状或呼吸困难 | |
| GHS 分类：特定靶器官毒性，单次暴露，呼吸道刺激，分类3 | |
| H335—可致呼吸道刺激 | |
| GHS 分类：生殖细胞的变异原性，分类2 | |
| H341—疑致遗传缺陷 | |
| GHS 分类：生殖毒性，分类2 | |
| H361—疑损伤生育能力或未出生的孩子 | |
| GHS 分类：特定靶器官毒性，单次暴露，呼吸道刺激，分类1 | |
| H370—致器官损害 | |
| GHS 分类：危害水生环境，长期危害，分类4 | |
| H413—可对水生生物造成长期危害 |
【关于每周分子 】
自2001年以来，“每周分子”已成为广受欢迎的栏目。多数分子由读者推荐。每个结构都经由科学家审查，并以3-D和平面图像的形式显示，同时附有该分子简介。可以通过美国化学文摘社（CAS）提供的SciFinder中的CAS REGISTRY获取每周分子的更多信息。CAS REGISTRY中的每条物质信息都展示了物质的CAS登记号、索引名、通用名、商品名、书目信息等其他更多信息。发送邮件至motw@acs.org推荐您感兴趣的分子。
Larotrectinib (tradename Vitrakvi) is a cancer drug that was discovered by Array BioPharma (Boulder, CO) in the 2000s. In 2013, Array licensed it to Loxo Oncology (Stamford, CT, and South San Francisco, CA). The drug was jointly developed by Loxo (now part of Eli Lilly [Indianapolis]) and Bayer AG (Leverkusen, Germany). In 2018, the US Food and Drug Administration approved larotrectinib for treating cancer patients with a certain genetic marker.
Larotrectinib is the second drug (after Merck’s Keytruda), and the first small molecule, to be approved as a “tissue-agnostic” drug by the FDA. Tissue-agnostic means that the drug is not directed at cancers in specific organs, but rather at cancers caused by particular genetic mutations.
One type of gene mutation produces tumors resulting from the fusion of enzymes in the tropomyosin kinase (TRK) family. Larotrectinib inhibits TRK fusions and shrinks tumors produced by many types of cancer.
As always, there’s a catch. Vitrakvi is outrageously expensive. The Loxo–Bayer partnership has set the monthly wholesale acquisition cost of Vitrakvi pills at US$32,800. The price of the liquid formulation (primarily for children) is somewhat lower at $11,000. The companies justify these prices because of the rarity of patients with TRK fusion mutations.
Larotrectinib fast facts
| CAS Reg. No. | 1223403-58-4 |
| Empirical formula | C21H22F2N6O2 |
| Molar mass | 428.44 g/mol |
| Appearance | Yellow powder |
| Melting point | Unavailable |
| Water solubility | Insoluble |
Larotrectinib hazard information
| GHS classification*: skin irritation, category 2 | |
| H315—Causes skin irritation | |
| GHS classification: skin sensitization, category 1 | |
| H317—May cause an allergic skin reaction | |
| GHS classification: serious eye damage/eye irritation, category 1 | |
| H318—Causes serious eye damage | |
| GHS classification: Respiratory sensitization, category 1 | |
| H334—May cause allergy or asthma symptoms or breathing difficulties if inhaled | |
| GHS classification: specific target organ toxicity, single exposure, respiratory tract irritation, category 3 | |
| H335—May cause respiratory irritation | |
| GHS classification: germ-cell mutagenicity, category 2 | |
| H341—Suspected of causing genetic defects | |
| GHS classification: reproductive toxicity, category 2 | |
| H361—Suspected of damaging fertility or the unborn child | |
| GHS classification: specific target organ toxicity, single exposure, category 1 | |
| H370—Causes damage to organs | |
| GHS classification: hazardous to the aquatic environment, long-term hazard, category 4 | |
| H413—May cause long-lasting harmful effects to aquatic life |
*Globally Harmonized System of Classification and Labeling of Chemicals. Explanation of pictograms.
About Molecule of the Week
MOTW has been a popular feature on ACS website since 2001. Many molecules are suggested by our website visitors. Every structure is reviewed by a scientist and displayed in 3-D and flat images with a brief description. Each week’s molecule also links to a sample record from the CAS REGISTRY, which is searched using SciFinder. Each record displays the registry number, index name and synonyms, bibliographic information, and more. Send us a molecule suggestion at motw@acs.org.
Copyright © 2019 American Chemical Society.
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