|OHSU and Aptose Present CG’806 Preclinical Data Demonstrating Potent Activity Against Patient Samples at AACR Hematologic Malignancies Meeting|
The poster, entitled CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes, demonstrated the broad potency of CG’806 against various hematologic malignancy cell lines and patient primary bone marrow specimens. In addition, data for CG’806 indicated greater potency of CG’806 when compared to other non-proprietary competitive agents in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), including the bromodomain inhibitors OTX-015 and JQ-1, and the FLT3 inhibitor quizartinib.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” said
"These findings further strengthen our commitment to develop CG’806 as a targeted treatment for AML and other hematologic malignancies," commented
Through the Beat AML Initiative, primary patient mononuclear cells were derived from 82 patients diagnosed with AML. Primary samples were also collected from patients with myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN, n=15), acute lymphoblastic leukemia (ALL, n=17), and chronic lymphocytic leukemia (CLL, n=58). Sensitivity to CG’806 was evaluated across a range of concentrations after a 72-hour treatment. IC50 values were calculated as a measure of drug sensitivity and compared to other agents.
Across the four general subtypes of hematologic malignancies in the dataset, there was broad sensitivity to CG’806, with 59% (48/82) of AML, 29% (5/17) of ALL, 53% (8/15) of MDS/MPN, and 40% (23/58) of CLL cases exhibiting an IC50 of less than 100 nM. Primary AML and CLL cells were sensitive to CG’806 with median IC50 values of 70 nM and 220 nM, respectively. Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30). CG’806 also exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt’s lymphoma, and diffuse large B-cell lymphoma cell lines. In comparison to the FLT3 inhibitor quizartinib, CG’806 completely inhibited phosphorylation of FLT3 and STAT5 in MV4-11 cells, whereas quizartinib only partially inhibited their phosphorylation.
The presentation will be published in the AACR Hematologic Malignancies Conference Proceedings. The poster can also be accessed here or at the Publications & Presentations section of the Aptose website, www.aptose.com.
CG’806 is a once-daily, oral, first-in-class pan-FLT3/BTK inhibitor. This small molecule demonstrates potent inhibition of mutant forms of FLT3 (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 Cys481Ser mutant 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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