Mitoxantrone and abacavir: An ALK protein-targeted in silico proposal for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a type of lung cancer associated with translocation of the EML4 and ALK genes on the short arm of chromosome 2. This leads to the development of an aberrant protein kinase with a deregulated catalytic domain, the cdALK+. Currently, different ALK inhibitors (iALKs) have been proposed to treat ALK+ NSCLC patients. However, the recent resistance to iALKs stimulates the exploration of new iALKs for NSCLC. Here, we describe an in silico approach to finding FDA-approved drugs that can be used by pharmacological repositioning as iALK. We used homology modelling to obtain a structural model of cdALK+ protein and then performed molecular docking and molecular dynamics of the complex cdALK+-iALKs to generate the pharmacophore model. The pharmacophore was used to identify potential iALKs from FDA-approved drugs library by ligand-based virtual screening. Four pharmacophores with different atomistic characteristics were generated, resulting in six drugs that satisfied the proposed atomistic positions and coupled at the ATP-binding site. Mitoxantrone, riboflavin and abacavir exhibit the best interaction energies with 228.29, 165.40 and 133.48 KJoul/mol respectively. In addition, the special literature proposed these drugs for other types of diseases due to pharmacological repositioning. This study proposes FDA-approved drugs with ALK inhibitory characteristics. Moreover, we identified pharmacophores sites that can be tested with other pharmacological libraries.

Prevalence and Prognosis of Secondary Genetic Aberrations Among Patients With Core Binding Factor Acute Myeloid Leukemia: A Mitelman Database Analysis.

Background: Core binding factor acute myeloid leukemia (CBF-AML) comprises t(8;21) and inv(16) and usually has a favorable prognosis. However, a wide spectrum of secondary genetic aberrations has been shown to be associated with worse outcomes with respect to overall survival (OS) and relapse. We aimed to identify secondary molecular and chromosomal aberrations within each group of CBF-AML, i.e., t(8;21) and inv(16), and to evaluate their prognosis with OS. Methods: Using the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, we analyzed 193 cases of CBF-AML reported between 2011 and 2021. We conducted a survival analysis to determine the 5-year OS, and we conducted univariate and multivariate Cox regression to identify independent genetic factors related to OS. Results: Among the 193 cases with CBF-AML, structural and numerical chromosome rearrangements were 25.9% and 40.9%, respectively, and secondary genetic mutations were 54.9%. The 5-year OS for the presence of del(7) and trisomy 22 was significantly worse. NRAS mutations had a worse 5-year OS in the t(8;21) group in the univariate analysis but showed no significant difference in the multivariate analysis. Conclusions: CBF-AML has heterogeneous cytogenetic characteristics but no difference in the 5-year OS between the inv(16) and t(8;21) groups. Finally, the presence of del(7), trisomy 22 and NRAS mutations showed a potential prognostic impact in CBF-AML patients. Secondary genetic findings may need to be identified to determine its association to a worse prognosis, and in the future develop better targeted therapies in patients with CBF-AML.