Asciminib is the first-in-class Specifically Targeting the ABL1 Myristoyl Pocket (STAMP) inhibitor, which was granted accelerated approval in 2021 for patients with Philadelphia chromosomepositive (Ph+) chronic myeloid leukemia (CML) in chronic phase, previously treated with two or more tyrosine kinase inhibitors (TKIs), and for adult patients with Ph+ CML in chronic phase with the T315I mutation. Asciminib binds to a myristoyl site of the BCR-ABL1 protein and locks the protein into an inactive conformation through a mechanism distinct from those of all other orthosteric TKIs such as imatinib, thus overcoming drug resistance arising from ATPbinding site mutations. Asciminib mimics the function of the myristoylated N-terminus of ABL1 and restores the natural autoinhibition of the ABL1b protein.
Asciminib comprises ABL kinase inhibitors and/or SLC7A11 inhibitors for the treatment of cancer and central nervous system (CNS) disorders.
Asciminib (Scemblix) is a drug used to treat hematological malignancies, including Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). It is indicated for the treatment of adult patients with Ph+ CML chronic phase (CML-CP) who have received at least 2 TKIs, and adult patients with Ph+ CML-CP who carry the T315I mutation.
Class: non-receptor tyrosine kinase
Treatment: CML
Elimination half-life = 14.2 h
Protein binding = 97%
Asciminib showed potent activity against multiple single catalytic site mutations, including the T315I mutation, which have led to resistance to traditional TKIs. Unlike conventional TKIs, Asciminib inhibits cancer cell proliferation by targeting the myristoyl pocket of BCR-ABL1 tyrosine kinase rather than the ATP binding site.
The synthesis of asciminib hydrochloride was based on bromonicotinate 30.3. 30.3 can be prepared by SNAr reaction of chiral pyrrolidinol 30.2 with chloronicotinate 30.1. Suzuki cross-coupling of 30.3 with boronate 30.4 gave pyrazolenicotinate 30.5 on a 50 kg scale, which was subsequently treated with the free base of aniline 30.6 in the presence of potassium tert-butoxide to afford 30.8 from boronate 30.4 in 79-87% yields. Deprotection of the tetrahydropyranyl group was achieved by exposure to 37% HCl in MeOH, and the free base crystallized in 76% yield after adjusting the pH with sodium hydroxide. Asciminib hydrochloride (30) was then generated by addition of hydrochloric acid and crystallized in high yield from MeOH and MTBE.
Asciminib is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Single doses of 7.5, 15 and 30 mg/kg ABL001, administered to mice bearing KCL- 22 xenografts, inhibits pSTAT5 (Tyr694), which return to baseline at 10, 12 and 16-20h after administration of the dose, respectively. In mice implanted with KCL-22 tumors, the minimum dose of asciminib required for complete regression is 7.5 mg/kg twice a day (BID) or 30 mg/kg once a day (QD), and is tolerated at doses up to 250 mg/kg BID. Similarly, in xenografts derived from patients, treatment with 7.5 and 30 mg/kg asciminib leads to regressions that are maintained during dosing[1].
