The p210 protein is a constitutively active, non-receptor tyrosine kinase that phosphorylates its Tyr177 residue, which subsequently activates a number of downstream signaling pathways that causes HSC cells undergo significant abnormal proliferation and differentiation compared to normal cells, producing the pathogenic changes reported in CML patients ( Deininger et al., 2000 Gora-Tybor and Robak, 2008 Cao et al., 2015 Wang et al., 2016). The p210 protein occurs was observed in more than 90% of CML patients and has been hypothesized to be the initial step in the pathogenesis of CML ( Arana-Trejo et al., 2002). Typically, the most common BCR-ABL proteins produced in CML patients, based on the loci of the chromosomal breaks, are p210, p190, and p230 ( Winter et al., 1999 Arana-Trejo et al., 2002). Our results suggest that ZINC21710815 may be a potential BCR-ABL inhibitor that should undergo in vivo evaluation.Р”В¬hronic myelogenous leukemia (CML) is a hematopoietic neoplastic disease that primarily results from the reciprocal translocation between chromosomes 9 and 22 (t9 22) (q34 q11) in a hematopoietic stem cell (HSC), resulting in the formation of the bcr-abl oncogene ( Deininger et al., 2005 Ren, 2005 Kimura, 2006). The compound ZINC21710815 decreased the expression of p-BCR-ABL, STAT5, and Crkl and produced apoptosis and autophagy. 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 hit compounds were further screened using LipinskiРІР‚в„ўs rule of five, ADMET and molecular docking, and the efficacy of the hit compounds was evaluated. We also used optimal pharmacophore models such as three-dimensional queries to screen the ZINC database to search for potential BCR-ABL inhibitors. 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. Therefore, there is the need to develop novel compounds that can overcome these problems that limit the use of these drugs. 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. This protein has constitutive tyrosine kinase activity that activates numerous downstream pathways that ultimately produces uncontrolled myeloid proliferation.

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.

Issues with bcr 2000