Abstract
Simple SummaryCDDD11-8 is an orally bioactive pharmacological inhibitor of CDK9. In AML cells, CDDD11-8 suppressed the proliferation and caused robust inhibition of tumor growth in vivo via synergistic inhibition of FLT3. The drug candidate has potential to overcome cancer cell resistance to FLT3 inhibition by concurrently blocking the CDK9-mediated upregulation of cancer cell-survival genes.Mutations in FMS-like tyrosine kinase 3 (FLT3) occur in approximately one-third of AML patients and are associated with a particularly poor prognosis. The most common mutation, FLT3-ITD, is a self-activating internal tandem duplication (ITD) in the FLT3 juxtamembrane domain. Many FLT3 inhibitors have shown encouraging results in clinical trials, but the rapid emergence of resistance has severely limited sustainable efficacy. Co-targeting of CDK9 and FLT3 is a promising two-pronged strategy to overcome resistance as the former plays a role in the transcription of cancer cell-survival genes. Most prominently, MCL-1 is known to be associated with AML tumorigenesis and drug resistance and can be down-regulated by CDK9 inhibition. We have developed CDDD11-8 as a potent CDK9 inhibitor co-targeting FLT3-ITD with Ki values of 8 and 13 nM, respectively. The kinome selectivity has been confirmed when the compound was tested in a panel of 369 human kinases. CDDD11-8 displayed antiproliferative activity against leukemia cell lines, and particularly potent effects were observed against MV4-11 and MOLM-13 cells, which are known to harbor the FLT3-ITD mutation and mixed lineage leukemia (MLL) fusion proteins. The mode of action was consistent with inhibition of CDK9 and FLT3-ITD. Most importantly, CDDD11-8 caused a robust tumor growth inhibition by oral administration in animal xenografts. At 125 mg/kg, CDDD11-8 induced tumor regression, and this was translated to an improved survival of animals. The study demonstrates the potential of CDDD11-8 towards the future development of a novel AML treatment.
Highlights
Kinase inhibition, as a molecularly targeted therapy, has become a rapidly growing field in oncology due to an ever-increasing understanding of the role of kinases in pivotal oncogenic pathways
CDDD11-8 is a potent inhibitor of CDK9 and FMS-like tyrosine kinase 3 (FLT3)
The apoptotic mechanism of CDDD11-8 was linked with cleavage of caspase 3 and PARP (Figure 3A,B). These results indicated that CDDD11-8 is most likely to induce apoptosis in the leukemia cell lines by modulating the cellular activity of CDK9 and FLT3
Summary
As a molecularly targeted therapy, has become a rapidly growing field in oncology due to an ever-increasing understanding of the role of kinases in pivotal oncogenic pathways. One of the hallmarks of cancer cell transformation is the accumulation of gene mutations leading to the simultaneous activation of multiple pathways involved in proliferation and/or survival. Gain-of-function mutations of FLT3 by internal tandem duplication (ITD) in the juxtamembrane domain or point mutations in its tyrosine kinase domains (FLT3-TKD) were found in approximately 30 to 40% of AML patients, engendering poor prognostic outcomes [4,6]. These constitutively active variants of FLT3 drive the sustained proliferation of early hematopoietic cells [4,6]. The overall clinical responses with these targeted inhibitors have been found to be transient due to the eventual development of primary or acquired resistance [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
