TMP195

TMP195 has low potency in recombinant class I and IIb HDAC assays, enabling full inhibition of class IIa HDAC activity without inhibition of other HDACs. TMP195 blocks the accumulation of CCL2 protein in the supernatants of monocyte-derived macrophage differentiation cultures and significantly increases the amount of CCL1 protein secreted by the monocytes compared to vehicle (DMSO)-treated M-CSF plus GM-CSF cultures^[1]. TMP195 influences human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro^[2].

Monocytes were differentiated into antigen presenting cells in RPMI Medium 1640 supplemented with GlutaMAX fetal bovine serum (10% v/v), IL-4 (10 ng/ml), GM-CSF (50 ng/ml), penicillin (100 U/ml), and streptomycin (100 μg/ml) for 5 days in the presence of either 0.1% (v/v) DMSO or 300 nM TMP195. Cells were collected by washing and incubation with a solution of 5 mM EDTA in PBS (Ca2+/Mg2+-free), before flow cytometric analysis.

In vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. TMP195 treatment significantly decreases proliferating tumour cells, most notably at the leading edge of the tumour. The anti-tumour macrophage phenotype induced by TMP195 treatment thus enhances the efficacy and durability of both standard chemotherapeutic regimens and checkpoint blockade immunotherapy in this mouse model of breast cancer^[2].