The novel IAP inhibitor, LCL161, [corrected] was observed to potentiate the effects of tyrosine kinase inhibition against leukemic disease both in the absence and presence of a stromal-protected [corrected] environment. LCL161 enhanced the proapoptotic effects of nilotinib and PKC412, against leukemic disease in vitro and potentiated the activity of both kinase inhibitors against leukemic disease in vivo. In addition, LCL161 synergized in vivo with nilotinib to reduce leukemia burden significantly below the baseline level suppression exhibited by a moderate-to-high dose of nilotinib. Finally, LCL161 displayed antiproliferative effects against cells characterized by intrinsic resistance to tyrosine kinase inhibitors as a result of expression of point mutations in the protein targets of compound inhibition.T lymphocytes treated with LCL161 demonstrated significantly enhanced cytokine secretion upon activation, with little effect on CD4 and CD8 T-cell survival or proliferation. LCL161 treatment of peripheral blood mononuclear cells significantly enhanced priming of naïve T cells with synthetic peptides in vitro. LCL161 may be a useful agent in combination with paclitaxel to treat liver tumours.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors.
Infante JR, et al. J Clin Oncol. 2014 Oct 1;32(28):3103-10. PMID: 25113756.
Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells.
Tian A, et al. Cancer Lett. 2014 Sep 1;351(2):232-41. PMID: 24976294.
Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy.
Knights AJ, et al. Cancer Immunol Immunother. 2013 Feb;62(2):321-35. PMID: 22923192.
Smac mimetics: implications for enhancement of targeted therapies in leukemia.
Weisberg E, et al. Leukemia. 2010 Dec;24(12):2100-9. PMID: 20844561.
|Related IAP Products|
SM-164 is a potent cell-permeable and bivalent Smac mimetic which bind to a XIAP protein with a Ki value of 0.56 nM, and binds to cIAP-1 and cIAP-2 proteins with Ki values of 0.31 and 1.1 nM, respectively.
BV6 is a small-molecule Smac mimetic, which antagonizes IAP proteins.
Birinapant (formerly TL32711) is a Smac mimetic acts as antagonist to cIAP1 and cIAP2.
GDC-0152 is a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins with potential antineoplastic activity.
AT-406 is an orally bioavailable potent IAP (inhibitor of apoptosis protein) of XIAP, cIAP1 and cIAP2 with Ki of 66.4 nM, 1.9 nM and 5.1 nM, respectively.
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