Comprehensive Monograph on the Investigational Agent 7-Hydroxystaurosporine (UCN-01)

Executive Summary

7-Hydroxystaurosporine, known predominantly by its code name UCN-01, is an investigational small molecule antineoplastic agent belonging to the indolocarbazole class of alkaloids.[1] Initially isolated from

Streptomyces sp. and subsequently developed as a synthetic derivative of the natural product staurosporine, UCN-01 was first characterized as a selective inhibitor of Protein Kinase C (PKC).[1] Further investigation, however, revealed it to be a potent, non-selective, ATP-competitive inhibitor of a broad spectrum of protein kinases critical to cell cycle control and survival signaling pathways.[5] Its primary molecular targets include multiple isoforms of PKC, various Cyclin-Dependent Kinases (CDKs), the pivotal DNA damage checkpoint kinase Chk1, and key components of the PI3K/Akt survival pathway, such as PDK1 and Akt itself.[7]

The compound's cellular pharmacology is characterized by a notable dual mechanism of action. As a monotherapy, it induces a cytostatic G1/S phase cell cycle arrest by inhibiting G1 CDKs and preventing the phosphorylation of the Retinoblastoma protein.[1] In contrast, when administered following DNA-damaging agents like cisplatin or radiation, it acts as a potent cytotoxic sensitizer by abrogating the S and G2 checkpoints, primarily through Chk1 inhibition. This forces damaged cells into a lethal mitosis, providing a strong rationale for its development in combination therapies.[8]