An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells.

An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells. Bioorg Med Chem Lett. 2019 Jul 27;: Authors: Hayatigolkhatmi K, Padroni G, Su W, Fang L, Gómez-Castañeda E, Hsieh YC, Jackson L, Pellicano F, Burley GA, Jørgensen HG Abstract Tyrosine kinase inhibitor (TKI) therapy is the standard treatment for chronic phase (CP)-chronic myeloid leukemia (CML), yet patients in blast crisis (BC) phase of CML are unlikely to respond to TKI therapy. The transcription factor E2F1 is a down-stream target of the tyrosine kinase BCR-ABL1 and is up-regulated in TKI-resistant leukemia stem cells (LSC). Pyrrole imidazole polyamides (PA) are minor groove binders which can be programmed to target DNA sequences in a gene-selective manner. This manuscript describes such an approach with a PA designed to down-regulate E2F1 controlled gene expression by targeting a DNA sequence within 100 base pairs (bp) upstream of the E2F1 consensus sequence. Human BC-CML KCL22 cells were assessed after treatment with PA, TKI or their combination. Our PA inhibited BC-CML cell expansion based on cell density analysis compared to an untreated control after a 48-hour time-course of PA treatment. However, no evidence of cell cycle arrest was observed among BC-CML cells treated with PA, with respect to their no drug control counterparts. Thus, this work demonstrates that...
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Tags: Bioorg Med Chem Lett Source Type: research