TNG260 is a selective, orally effective inhibitor of HDAC1 and CoREST complex, with a 10-fold selectivity for HDAC1 over HDAC3 and a 500-fold selectivity for CoREST complex over NuRD and Sin3 complex. TNG260 reshapes the tumor immune microenvironment, reduces immunosuppressive neutrophil infiltration, promotes effector T cell recruitment, and reverses anti-PD-1 resistance caused by STK11 deficiency by inhibiting the activity of the CoREST-HDAC1 complex. TNG260 induces durable tumor regression in combination with α-PD1 in MC38 tumor-bearing mice with STK11 mutations, and has lower toxicity to bone marrow cells than non-selective HDAC inhibitors.
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