Technology

Technology

INTH-454 is a novel synthetic small molecule which inhibits the growth and induces cell death in a broad range of tumor cells. Hereby, it acts particularly on cancer cells with a high proliferative potential by binding to the Negative Elongation Factor complex of transcription NELF, leading to altered transcriptional control, introducing replicative stress and inhibiting DNA synthesis, resulting in death of tumor cells.

NELF is a four-subunit protein complex, consisting of NELFA, NELFB=COBRA1 (Co-factor of BRCA1), NELFC/NELFD (encoded by the same gene), and NELFE, that negatively impacts elongation of transcription through RNA polymerase II (Pol II) by pausing transcription about 20-60 nucleotides downstream from the transcription start site, generating a cellular checkpoint of transcriptional processes.

After inactivation of NELF by singaling pathways controlled by proteins including BRD4 and CDK9, elongation of transcription of target genes takes place. 

INTH-454 strongly inhibits tumor growth in various mouse models of human cancers, e.g., strong anti-tumor activity has been shown for INTH-454 in representative mouse models of, e.g., prostate cancer, small cell lung cancer and gastric (stomach) tumors as displayed below.



Most potent effects have been observed in tumors/cell lines which display particularly high proliferative potential and in which a dysregulation of the G1/S cell cycle checkpoint can be identified.   

Inthera currently plans to enter INTH-454 into clinical development in 2023 with an initial focus for the treatment of patients with advanced stages of prostate cancer (CRPC), and also for patients with advanced small cell lung cancer (SCLC).