Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models.

CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 µM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

Immunomodulator FTY720 improves glucose homeostasis and diabetic complications by rejuvenation of ß-cell function in nonhuman primate model of diabetes.

Inadequate ß-cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, sustainably normalized hyperglycemia by stimulating ß-cell in vivo regeneration in db/db mice. We further examined the effects of FTY720 on glucose homeostasis and diabetic complications in a translational nonhuman primate (NHP) model of spontaneously developed diabetes. The male diabetic cynomolgus macaques of 18-19 year old were randomly divided into Vehicle (Purified water, n = 5) and FTY720 (5 mg/kg, n = 7) groups with oral gavage once daily for 10 weeks followed by 10 weeks drug free period. Compared with the Vehicle group, FTY720 effectively lowered HbA1c, blood concentrations of fasting glucose (FBG) and insulin, hence, decreased homeostatic model assessment of insulin resistance (HOMA-IR); ameliorated glucose intolerance and restored glucose-stimulated insulin release, indicating rejuvenation of ß-cell function in diabetic NHPs. Importantly, after withdrawal of FTY720, FBG, and HbA1c remained at low level in the drug free period. Echocardiography revealed that FTY720 significantly reduced proteinuria and improved cardiac left ventricular systolic function measured by increased ejection fraction and fractional shortening in the diabetic NHPs. Finally, flow cytometry analysis (FACS) detected that FTY720 significantly reduced CD4 + and CD8 + T lymphocytes as well as increased DC cells in the circulation. Immunomodulator FTY720 improves glucose homeostasis via rejuvenation of ß-cell function, which can be mediated by suppression of cytotoxic CD8 + T lymphocytes to ß-cells, thus, may be a novel immunotherapy to reverse T2D progression and ameliorate the diabetic complications.