Small molecule therapies with expansive potential

Accent’s second lead program is a potential best-in-class inhibitor for KIF18A which may address a large patient population across several cancer indications, including ovarian and triple negative breast cancer (TNBC). KIF18A is a mitotic kinesin motor protein critical for cell division in select tumors with chromosomal instability. Studies have confirmed a subset of tumor cells with an abnormal number of chromosomes (aneuploid) are sensitive to KIF18A and show rapid cell killing in vitro and in vivo upon KIF18A inhibitor treatment, while cells with normal numbers of chromosomes (euploid) are unaffected.

Accent has advanced this program quickly and will initiate IND-enabling studies in the first half of 2024. We are currently investigating biomarker hypotheses to more fully define the patient population that will benefit most from this treatment.

Accent is developing first-in-class small molecule inhibitors of ADAR1, a historically challenging, high-value oncology target with substantial opportunity for use as a monotherapy in many solid tumor indications with significant unmet need — including non-small cell lung cancer, triple-negative breast cancer, ovarian cancer, and head and neck squamous cell carcinomas.

Data shows that cancers refractory to PD-1 inhibition and those that relapse following PD-1 treatment may be acutely sensitive to ADAR1 inhibition, suggesting that small molecule inhibitors of ADAR1 have further potential to combine well with checkpoint inhibitors to treat PD-1 and PD-L1 relapse/refractory tumors.

ADAR1 is an adenine deaminase that modifies double-stranded RNA to prevent triggering of immune response through naturally occurring, innate pathways. In tumor cells with higher IFN signaling, small molecule inhibitors of ADAR1 induce selective cell killing and immune sensitization. ADAR’s potential as a monotherapy and in combination with immuno-oncology therapies make it a highly attractive target.

Within Accent’s pipeline, we are developing inhibitors of XRN1, an RNA exonuclease for which tumors with higher IFN signaling are acutely sensitive. XRN1 has the potential as a monotherapy, and in combination with immuno-oncology therapeutics.