The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach

Abstract

Chronic myelogenous leukemia (CML) typically results from a reciprocal translocation between chromosomes 9 and 22 to produce the bcr-abl oncogene that when translated, yields the p210 BCR-ABL protein in more than 90% of all CML patients. This protein has constitutive tyrosine kinase activity that activates numerous downstream pathways that ultimately produces uncontrolled myeloid proliferation. Although the use of the BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib have increased the overall survival of CML patients, their use is limited by drug resistance and severe adverse effects. Therefore, there is the need to develop novel compounds that can overcome these problems that limit the use of these drugs. Therefore, in this study, we sought to find novel compounds using Hypogen and Hiphip pharmacophore models based on the structures of clinically approved BCR-ABL TKIs. We also used optimal pharmacophore models such as three-dimensional queries to screen the ZINC database to search for potential BCR-ABL inhibitors. The hit compounds were further screened using Lipinski’s rule of five, ADMET and molecular docking, and the efficacy of the hit compounds was evaluated. Our in vitro results indicated that compound ZINC21710815 significantly inhibited the proliferation of K562, BaF3/WT, and BaF3/T315I leukemia cells by inducing cell cycle arrest. The compound ZINC21710815 decreased the expression of p-BCR-ABL, STAT5, and Crkl and produced apoptosis and autophagy. Our results suggest that ZINC21710815 may be a potential BCR-ABL inhibitor that should undergo in vivo evaluation.

Pharmacophore-Based Virtual Screening of Potential SARS-CoV-2 Main Protease Inhibitors from Library of Natural Products

“…Other parameters, such as the correlation coefficient and RMS deviation value, were used to evaluate the ability of a pharmacophore model to predict the activity of training set molecules. 21 The first model (Hypo1) among the 10 generated pharmacophore models had the highest cost difference (735.01), lowest RMS deviation (1.5433), and best correlation coefficient (0.982). Therefore, Hypo1 was selected as the signified pharmacophore 1 shows the 3D spatial arrangement of Hypo1 and its alignment with the most active compound (IC 50 = 0.0076 μM) in the training set.…”

Mechanism insights of curcumin and its analogues in cancer: An update

“…It has been evidenced that both XIAP and cellular inhibitor of apoptosis protein 1 (cIAP1) play a major role in the degradation of Bcr-Abl protein. Consistent with Bcr-Abl degradation, SNIPER(Abl)-39 inhibits the STAT5 and Crk-like proto-oncogene (CrkL) phosphorylation in Bcr-Abl-positive CML cells(Huang et al, 2021;Rossari et al, 2018;Shibata et al, 2017) (Figure3). Curcumin analogue C817 (81) is accounted to repress both WT and freak (T315I, Y253F, and Q252H) Abl kinase exercises in a non-ATP way.…”

PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy

“…Constitutively active BCR-ABL signals through downstream pathways or effectors including MAPK, PI3K-Akt, STAT5, and CrkL to promote carcinogenesis [ 218 ]. FDA approved occupancy-based BCR-ABL inhibitors include (i) first generation imatinib which only binds when the activation loop is in the closed (inactive) position; (ii) second generation dasatinib, nilotinib, and bosutinib which bind irrespective of the activation loop position; (iii) third generation ponatinib which remains active against the T315I mutation; and (iv) allosteric (myristoyl-binding regulatory pocket) inhibitor asciminib [ 219 , 220 ]. Resistance to BCR-ABL inhibition is typically due to point mutations in the P-loop or ATP-binding pocket, gene amplification, drug efflux, or BCR-ABL-independent mechanisms [ 18 ].…”