Precision Small-Molecule Targeting Cancers Deficient in Nucleotide-Excision Repair

Novel Approaches, Targets, and Therapeutics

Michael Kelner, MD (Illudent)

Sean Uryu (Illudent)

Venkata Kotaraju (Illudent)

Solid tumors with loss-of-function (LOF) mutations in nucleotide-excision repair (NER) genes—particularly ERCC2—are highly sensitive to illudins. Our lead compound, ITX-121, has shown the best therapeutic index in its class (illudins) based on prior in vitro and in vivo studies. We hypothesize that ITX-121 will demonstrate strong efficacy with minimal toxicity in ERCC2-mutant PDO and PDX models, supporting advancement to clinical development. Methods, Aims, and Expected Outcomes Using CROs (Including Certis and Crown in San Diego), we will test ITX-121 in ERCC2-mutant patient-derived organoids (PDOs) in vitro, followed by patient-derived xenografts (PDXs) in vivo. Our goal is to confirm that ITX-121 selectively targets ERCC2-mutant tumors with minimal toxicity, establishing a preclinical foundation for first-in-human trials. We will perform additional, similar work in ERCC6-mutant melanoma.