Abstract 791: CG'806, a first-in-class pan-FLT3/pan-BTK inhibitor, demonstrates superiority to other FLT3 and BTK inhibitors against primary patient samples
Authors: Kurtz Stephen E. , Watanabe-Smith Kevin , Bottomly Dan , Wilmot Beth , Mcweeney Shannon , Local Andrea , Zhang Hongying , Howell Stephen , Rice William , Druker Brian J. , Tyner Jeffrey W. 
Published: August 2018

Abstract
Introduction: While acute myeloid leukemia (AML) is a complex and heterogeneous malignancy, the most common mutation is the internal tandem duplication (ITD) of FLT3 occurring in ~30% of AML patients. Several FLT3 inhibitors have transient clinical benefit, lasting only 3-4 months, often due to emergence of drug resistant clones with additional mutations in FLT3. Thus, there is need for a pan-FLT3 inhibitor to control all mutant forms of FLT3, and to suppress diverse oncogenic clones. Likewise, overexpression of Bruton's tyrosine kinase (BTK) is a driver of chronic lymphocytic leukemia (CLL). Ibrutinib, a covalent BTK inhibitor approved for CLL and certain other B-cell malignancies, is limited by resistance resulting from mutation at cysteine residue 481 to serine (BTK-C481S), prompting a need for new agents to inhibit all forms of BTK.
CG'806 is a small molecule that inhibits wild type (WT) FLT3, FLT3-ITD and tyrosine kinase domain (TKD) point mutations, including D835G, D835Y, D835H, F691L; it also inhibits BTK WT and BTK-C481S. We profiled CG'806 against primary samples from patients with AML, CLL and other hematologic malignancies to determine its activity and potency relative to other FLT3 inhibitors. CG'806 and ibrutinib were compared directly for sensitivities on primary CLL samples and various B-cell and other hematologic malignancies.
Methods: Inhibitor activity was assessed by an ex vivo assay to determine sensitivities of CG'806 and other FLT3 and BTK inhibitors on freshly isolated primary patient samples. Cell viability was assessed after 72-hour culture using a tetrazolium-based MTS assay and IC50 values calculated as a measure of drug sensitivity. For AML samples, mutational status of ITD and TKD in FLT3 were assessed by a PCR assay for ITD and by whole exome sequencing for TKD.
Results: CG'806 has more potent activity against a broader subset of AML samples relative to other FLT3 inhibitors, including midostaurin, gilteritinib, quizartinib, sorafenib, crenolanib, and dovitinib. This was especially true in FLT3-ITD and FLT3-TKD positive cases, although enhanced activity was also observed in FLT3 WT samples. CG'806 potency correlated with FLT3-ITD allele frequency as cases with higher allelic frequency generally had greater sensitivity in comparison to lower allelic frequency cases. CG'806 had greater activity on primary CLL samples than ibrutinib, which may be due to the dual activity of CG'806 against CSF1R (FMS) (IC50 = 0.6nM), a recently described target in CLL that provides a pro-tumor signal from nurse-like monocyte/macrophage lineage cells.
Conclusions: CG'806 is a potent and broadly active FLT3 inhibitor in AML and BTK inhibitor in CLL. These data reveal CG'806's enhanced activity relative to kinase inhibitors currently approved for each indication and support further clinical development of CG'806 for both AML and CLL.
Citation Format: Stephen E. Kurtz, Kevin Watanabe-Smith, Dan Bottomly, Beth Wilmot, Shannon Mcweeney, Andrea Local, Hongying Zhang, Stephen Howell, William Rice, Brian J. Druker, Jeffrey W. Tyner. CG'806, a first-in-class pan-FLT3/pan-BTK inhibitor, demonstrates superiority to other FLT3 and BTK inhibitors against primary patient samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 791.