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LDC1267 is a highly selective TAM kinase inhibitor with IC50 of < 5 nM, 8 nM, and 29 nM for Mer, Tyro3, and Axl, respectively.

LDC1267 preferentially inhibits Tyro3, Axl and Mer at low nano-molarity by tracer-based binding assays. Treatment of NKG2D- activated NK cells with LDC1267 indeed abolished the inhibitory effects of Gas6 stimulation; LDC1267 had no apparent additional effect in Cbl-b-deficient NK cells. Adoptive transfer of LDC1267-treated wild-type NK cells significantly increased the anti-tumour response to levels observed in mice transplanted with Cbl-b2/2 NK cells, but did not increase the anti-metastatic efficacy of Cbl-b-knockout NK cells, reinforcing the notion that Cbl-b acts downstream of TAM receptors for NK cell inhibition. [1]

In vivo, wild-type mice treated with LDC1267 showed enhanced cytotoxicity towards RMA cells overexpressing the NKG2D ligand Rae-1 (RMA-Rae1) to the same extent as C373AKI/KI mice, but had no effect on the already enhanced NK cytotoxicity in Cbl-b-mutant mice. LDC1267 markedly reduced metastatic spreading of melanomas; NK1.1 depletion abolished the therapeutic benefits of LDC1267. LDC1267 treatment significantly reduced the numbers and sizes of 4T1 micro-metastases in the liver, without any apparent effect on the primary vehicle LDC1267 mammary tumor. NK cell depletion using anti-asialoGM1 antibodies resulted in markedly enhanced 4T1 liver metastases and abolished the therapeutic benefits of LDC1267. Oral LDC1267 significantly reduced 4T1 liver micro-metastases. [1]

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