CoREST Program

The remarkable clinical activity of immuno-oncology therapies, specifically checkpoint inhibitors, comes from activating certain immune cells to kill cancer cells. However, loss-of-function mutations in STK11 and some other tumor suppressor genes are strongly associated with immune checkpoint inhibitor resistance. TNG260 is a novel small molecule inhibitor of the Co-repressor of Repressor Element-1 Silencing Transcription (CoREST) deacetylase complex. In combination with immune checkpoint blockade, this CoREST inhibitor is designed to address the unmet medical need of immunotherapy-resistant STK11-mutant cancers.

IMMUNE EVASION DRIVEN
BY TUMOR SUPPRESSOR GENE LOSS

IMMUNE EVASION DRIVEN<br>BY TUMOR SUPPRESSOR GENE LOSS

STK11 re-activation is not feasible

TNG260 REVERSES IMMUNE
EVASION DRIVEN BY STK11
MUTATIONS

TNG260 REVERSES IMMUNE<br>EVASION DRIVEN BY STK11<br> MUTATIONS

Selective CoREST inhibition in cancer cells enables immune-mediated cytotoxicity

OPPORTUNITY

Our synthetic lethal target discovery approach can be adapted to identify druggable tumor-intrinsic targets that do not kill cancer cells directly, but rather attract immune cells to destroy them. In preclinical studies we have shown that CoREST inhibition reverses the immune evasion effect of STK11 (serine-threonine kinase 11) loss-of-function mutations, which are present in approximately 15% of non-squamous lung and cervical cancers, 10% of carcinoma of unknown primary, 5% of breast cancers and 3% of pancreatic cancers.

TNG260

TNG260 is a novel CoREST inhibitor in preclinical development to reverse immune evasion in STK11 mutated cancers
Our state-of-the-art in vivo CRISPR discovery platform enabled the discovery of STK11 as a tumor suppressor that drives immune evasion when not functional in cancer cells.
We engineered a syngeneic mouse tumor model in which STK11 loss of function drives resistance to immune checkpoint blockade.
Using our in vivo CRISPR screen, HDAC1 is a target that demonstrated strong reversal of immune evasion caused by STK11 deletion. Though HDAC1 has three major complexes, TNG260 is highly selective and binds to only the CoREST complex. We believe this selectivity provides for less toxicity compared to other HDACs that were in development.
Treatment of the STK11-mutant mouse tumor model with TNG260 in combination with anti-PD1 caused complete regressions in 5/8 animals and deep regressions in the remainder
Immune memory was induced in all five animals with complete responses rendering them resistant to rechallenge with the original tumor
Dose escalation is ongoing

TNG260 IC50 5NM, 10X ISOFORM SELECTIVITY

5/8 mice had complete tumor regression at day 34, treatment discontinued at day 48
All mice with complete regression remained tumor free off treatment for 21 days
5/5 with complete regression rejected tumor reimplantation

Learn more about our approach.