: Asciminib, also known as ACP-196, is the FDA-approved low-molecular ABL kinase inhibitor. The ABL kinase is a non-receptor tyrosine kinase that helps in cell growth and survival and is a key player in the development of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The BCR-ABL fusion protein, which is formed by chromosomal translocation in CML and Ph+ ALL, results in the constitutive activation of ABL kinase, leading to uncontrolled cell growth and proliferation. To have a high binding affinity for the active site of the enzyme, structural biology and computer-aided drug design (CADD) concepts were applied to the design of asciminib so that it could specifically target the ABL kinase enzyme. The drug was synthesized and characterized in a laboratory. In its pharmacological studies, it has shown that asciminib is a potent and selective inhibitor of ABL kinase. Phase I clinical trials assessed its safety and efficacy, revealing that it is effective against tumors while causing minimal discomfort to patients. In addition to this, it was able to induce apoptosis and a cytogenetic response as well as inhibit the proliferation of CML and Ph+ALL cells in patients with CML. As this trial gave a positive response, phase II and III trials were conducted. In that sense, asciminib has shown to be highly effective, with response rates of over 90% in patients with these diseases. The safety and efficacy of asciminib were also evaluated in combination with other drugs, such as tyrosine kinase inhibitors and immunomodulatory drugs, and the results were promising. Overall, the discovery and development of asciminib showed that by using the concepts of pharmacology and CADD, a drug with a 90% positive rate response can be developed with a high tolerance level and lower side effects

中文翻译：

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Asciminib - ABL 激酶抑制剂治疗费城染色体阳性慢性粒细胞白血病：化学和药理学观点

：Asciminib，也称为 ACP-196，是 FDA 批准的低分子 ABL 激酶抑制剂。ABL 激酶是一种非受体酪氨酸激酶，有助于细胞生长和存活，是慢性粒细胞白血病 (CML) 和费城染色体阳性急性淋巴细胞白血病 (Ph+ALL) 发展的关键参与者。BCR-ABL 融合蛋白由 CML 和 Ph+ ALL 中的染色体易位形成，导致 ABL 激酶的组成型激活，导致细胞生长和增殖失控。为了对酶的活性位点具有高结合亲和力，将结构生物学和计算机辅助药物设计（CADD）概念应用于asciminib的设计中，使其能够特异性靶向ABL激酶。该药物是在实验室合成和表征的。药理学研究表明，asciminib 是一种有效的、选择性的 ABL 激酶抑制剂。一期临床试验评估了其安全性和有效性，表明它能有效对抗肿瘤，同时对患者造成的不适最小化。除此之外，它还能够诱导细胞凋亡和细胞遗传学反应，并抑制 CML 患者的 CML 和 Ph+ALL 细胞的增殖。由于该试验得到了积极的反应，因此进行了II期和III期试验。从这个意义上说，阿西米尼已被证明非常有效，对这些疾病患者的缓解率超过 90%。阿西米尼与其他药物（如酪氨酸激酶抑制剂和免疫调节药物）联合使用的安全性和有效性也得到了评估，结果令人鼓舞。总体而言，asciminib的发现和开发表明，利用药理学和CADD的概念，可以开发出具有90%阳性反应率、高耐受水平和较低副作用的药物