Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Arch Pharm (Weinheim). 2018 Oct;351(10):e1800037. doi: 10.1002/ardp.201800037. Epub 2018 Aug 12.
The introduction of tyrosine kinase inhibitors (TKIs) in the clinical management of oncological patients spread the light on the use of selective, rationally designed small molecules for the treatment of cancer. First-generation TKIs bared high response against these malignancies, although the unavoidable shadow of resistance limits their long-term efficacy. Non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, and it is the first cause of cancer deaths worldwide for men and women. Traditional chemotherapy is marginally effective against this form, and erlotinib and gefitinib were introduced as first-line treatments based on the observation that the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), is mutated in several cases and, thus, represents a druggable target. EGFR-mutant and anaplastic lymphoma kinase (ALK)-positive patients are more responsive to these treatments, even if secondary mutations causing resistance soon emerged. The efforts of medicinal chemists are currently oriented toward the development of new generations of TKIs overcoming these obstacles. We here overview the novel strategies from the point of view of the medicinal chemist: the rational structure-based drug design that led to the development of irreversible and non-ATP-competitive inhibitors. Such improvements parallel the novel therapeutic strategies adopted in the clinic, which are also discussed.
酪氨酸激酶抑制剂（TKIs）在肿瘤患者临床管理中的引入，为癌症的治疗带来了选择性、合理设计的小分子的应用。第一代 TKI 对这些恶性肿瘤具有很高的反应性，尽管不可避免的耐药性限制了它们的长期疗效。非小细胞肺癌（NSCLC）占肺癌病例的 85%，是男性和女性癌症死亡的首要原因。传统化疗对此类疾病的疗效有限，厄洛替尼和吉非替尼被引入作为一线治疗药物，这是基于观察到表皮生长因子受体（EGFR），一种受体酪氨酸激酶（RTK），在几种情况下发生突变，因此代表了一个可用药的靶点。EGFR 突变和间变性淋巴瘤激酶（ALK）阳性患者对这些治疗更敏感，即使随后出现导致耐药性的继发突变。药物化学家目前的努力方向是开发克服这些障碍的新一代 TKI。我们从药物化学家的角度概述了新的策略：基于结构的合理药物设计导致了不可逆和非 ATP 竞争性抑制剂的发展。这些改进与临床上采用的新治疗策略相平行，我们也对此进行了讨论。
