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|Aptose Presents New Preclinical Data on CG’806 pan-FLT3/pan-BTK Inhibitor at ASH 59th Annual Meeting|
The poster The Pan-FLT3/BTK Multi-Kinase Inhibitor CG’806 Induces AML Killing in FLT-Mutant and Wild Type Cells, and Exerts Synergistic Pro-Apoptotic Effects with Concomitant Targeting of Anti-Apoptotic Bcl-2 and/or Mcl-1 demonstrated pronounced anti-leukemia activity of CG’806 against a broad array of AML cells, including those with FLT3-wild type, FLT3 with single mutations, or with FLT3 harboring dual ITD plus D835 or ITD plus F691 mutations, and it demonstrated synergistic effects in combination with Bcl-2 or Mcl-1 inhibitors even in FLT3 mutated AML cells. CG’806 elicited its broad spectrum killing of AML cells through its ability to suppress the FLT3 pathway as well the BTK, AURK, AKT and ERK signaling pathways that are differentially operative in different AML cells. Notably, CG’806 maintained cytotoxic activity against AML cells in the presence of FLT3 ligand and bone marrow stromal cells, and CG’806 demonstrated dose-dependent in vivo antitumor activity in a circulating AML murine model.
The poster CG’806, a Novel Pan-FLT3/BTK Multi-Kinase Inhibitor, Induces Cell Cycle Arrest, Apoptosis or Autophagy in AML Cells Depending on FLT3 Mutation Status further elucidated the anti-leukemia effect of CG’806. CG’806 exerted profound suppression of cell proliferation through G1 cell cycle arrest and induction of apoptosis in FLT3-mutant AML cells, which is associated with inhibition of mutant FLT3 signaling and the downstream p-AKT/p-mTOR/cyclin D1/p-Rb signaling axis. In contrast, CG’806 exerted a G2/M arrest in FLT3-wildtype (WT) cells through inhibition of aurora (AURK) and BTK kinases and induction of non-apoptotic cell death (autophagy or polyploidy). CG’806 sensitized AML cells to standard chemotherapeutic agents cytarabine and idarubicin and significantly enhanced pro-apoptotic effects. Taken together, these data support the development of CG’806 for a diverse set of AML patients with FLT3-ITD, FLT3-ITD plus additional TKD/gatekeeper mutations, as well as FLT3-WT.
Data were presented by members of the research team led by
The poster presentations can be accessed on the Events & Presentations section of the Aptose website at the following link.
"As our mechanistic understanding of CG’806 grows, we are beginning to construct a framework of how a single molecule can inhibit specific clusters of kinases and kill a heterogeneous group of AML cells without observed toxicity to normal cells,” commented
In addition to the abstracts that were presented at ASH, two additional abstracts on CG’806 and two abstracts on APTO-253, Aptose’s small molecule c-Myc Inhibitor, have been published on the ASH abstracts site. All abstracts will become part of the permanent ASH and Blood abstracts archive.
CG‘806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor. This small molecule demonstrates potent inhibition of all wild type and mutant forms of FLT3 tested (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), eliminates AML tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with FLT3-driven AML. Likewise, CG’806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B cell malignancies, suggesting CG’806 may be developed for CLL and MCL patients that are resistant/refractory/intolerant to covalent BTK inhibitors.
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