The Story of New Anti-Cancer Drug-AOH1996

Do you know that new drug AOH 1996 is named by a cute American girl? About AOH 1996, there is an inspiring story as below:

In 1996, a girl was born in the American state of Indiana and her parents named her Anna Olivia Healey. Unfortunately, when Anna Olivia Healey was 9 years old, who died of neuroblastoma (a fatal cancer in children). Her parents, Steven and Barbara Healey, were into great sorrow, in memory of their daughter, they set up a fund to help find a way to fight this cruel disease. In 2005, a few months before Anna died, Professor Linda Malkas met with Anna's father (a researcher of City of Hope). She made every effort to tackle the disease, and the focus of her research shifted from breast cancer to neuroblastoma.

Neuroblastoma accounts for 8 percent of childhood tumors but it can cause 15% death rate for childhood tumor.

Anna Olivia Healey

Let’s have an brief introduction for City of Hope. It founded in 1913 and located in California, is now one of the largest cancer research and treatment organizations in the United States. At this point, the City of Hope began the road of magic medicine AOH1996 research and development.

From AOH1160 to AOH1996

Proliferating Cell Nuclear Antigen (PCNA) was first identified and named by Miyachi and others in 1978 in the serum of patients with SLE (systemic lupus erythematosus). PCNA is only present in normal proliferating eukaryotic cells. In particular, it is highly expressed in a variety of tumor cells and plays a key and necessary role in the process of DNA synthesis and repair.

PCNA has always been considered as an "unviable drug target". In 2018, Professor Markas and his colleagues developed a potent PCNA inhibitor AOH1160 targeting the L126-Y133 region of PCNA, which is more prone to protein-protein interactions, based on computer modeling and pharmacochemical strategies. The drug molecule can selectively kill multiple types of cancer cells at concentrations below micromoles without causing significant toxicity to multiple non-malignant cells.There is no significant toxicity at 2.5 times the effective dose.

However, in subsequent studies, it was found that AOH1160 had obvious metabolic problems, so researchers modified and improved AOH1160, and thus discovered AOH1996. The methoxy group at the terminal benzene intersite of AOH1996 prolongs the half-life of the compound, possibly because the methoxy group protects the benzene ring from hydroxylation by CYP enzymes.

The Structural Formula of AOH1160 and AOH1996

The target of AOH1996, PCNA, is widely expressed in a variety of tumor cells, and the researchers conducted related tests in more than 70 cancer cell lines and several normal control cells, such as breast cancer, prostate cancer, brain cancer, ovarian cancer, cervical cancer, skin cancer, lung cancer and other cells. It was found that the IC50 of AOH1996 for a variety of tumor cells was about 300nM, and the replication cycle of cancer cells was stagnated in G2/S phase or S phase. In contrast, AOH1996 showed no significant toxicity to normal cells, even at a concentration of 10μM.

At present, AOH1996 has successfully passed preclinical studies, and Phase I clinical trials are being conducted to verify its safety. Whether AOH1996 can successfully pass phase I~III clinical trials, which is the biggest test for AOH1996.