[Pharmacological and clinical profile of asciminib hydrochloride, a novel first-in-class tyrosine kinase inhibitor specifically targeting ABL myristoyl pocket].

On March 28th, 2022, asciminib hydrochloride (Scemblix® Tablets 20 |mg/40 |mg), the world's first tyrosine kinase inhibitor (TKI) specifically targeting the ABL myristoyl pocket (STAMP inhibitor), was approved for chronic myeloid leukemia (CML) resistant or intolerant to prior therapy. Asciminib specifically binds to the myristoyl pocket, an allosteric site of BCR::ABL1, and inhibits the ABL1 family molecules. In vitro and in vivo pharmacology studies demonstrated cell growth inhibition and antitumor effects of asciminib. The international phase I study for patients with chronic or accelerated phase CML investigated the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of asciminib monotherapy. However, the MTD was not reached, so and RDE was determined based on tolerability, safety, pharmacokinetics (PK) and preliminary efficacy data obtained by the time of the study. RDE was determined to be 40 |mg twice daily in chronic or accelerated phase CML without T315I mutation, and 200 |mg twice daily in chronic or accelerated phase CML with T315I mutation. The international phase III study for patients with chronic phase CML who were previously treated with ≥2 TKIs and resistant or intolerant to the recent treatment demonstrated the superiority of asciminib over bosutinib in achieving the primary endpoint of a major molecular response (MMR) at week 24. Regarding safety, the most common treatment-related adverse event in asciminib arm was thrombocytopenia, and others included neutropenia. Asciminib is expected to be a new treatment option for CML patients who have limited choices due to resistance or intolerance to previous therapies.

Synthesis and biological evaluation of novel radioiodinated benzimidazole derivatives for imaging α-synuclein aggregates.

α-Synuclein (α-syn) aggregates are commonly found in the brains of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB), and some other diseases. Therefore, in vivo imaging of α-syn aggregates would aid in drug development, early diagnosis, and monitoring of disease status. In order to develop imaging probes targeting α-syn aggregates, we synthesized and evaluated three novel radioiodinated benzimidazole (BI) derivatives for selective imaging of α-syn aggregates. In binding experiments, BI-2 exhibited the highest selective binding affinity for α-syn aggregates among the BI derivatives. In addition, BI-2 clearly stained Lewy bodies in PD brain sections, but did not label senile plaques deposited in AD brain sections. However, in the biodistribution study using normal mice, [125I]BI-2 did not demonstrate high brain uptake (0.56%ID/g at 2-min post-injection). Further structural modifications of the BI derivatives are needed, but the BI scaffold may be an attractive candidate for developing α-syn imaging probes.

Novel Benzothiazole Derivatives as Fluorescent Probes for Detection of ß-Amyloid and α-Synuclein Aggregates.

Deposits of ß-amyloid (Aß) and α-synuclein (α-syn) are the hallmark of Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. The detection of these protein aggregates with fluorescent probes is particularly of interest for preclinical studies using fluorescence microscopy on human brain tissue. In this study, we newly designed and synthesized three push-pull benzothiazole (PP-BTA) derivatives as fluorescent probes for detection of Aß and α-syn aggregates. Fluorescence intensity of all PP-BTA derivatives significantly increased upon binding to Aß(1-42) and α-syn aggregates in solution. In in vitro saturation binding assays, PP-BTA derivatives demonstrated affinity for both Aß(1-42) (Kd = 40-148 nM) and α-syn (Kd = 48-353 nM) aggregates. In particular, PP-BTA-4 clearly stained senile plaques composed of Aß aggregates in the AD brain section. Moreover, it also labeled Lewy bodies composed of α-syn aggregates in the PD brain section. These results suggest that PP-BTA-4 may serve as a promising fluorescent probe for the detection of Aß and α-syn aggregates.