Asciminib - ABL Kinase Inhibitor in the Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia: Chemistry and Pharmacology Perspectives

Abstract: 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