Filenews 30 October 2021
Many cancer-related proteins are considered "drug-independent" because it is chemically difficult for a drug to activate or disable them.
The usual tactics for dealing with such persistent targets focuses on harnessing a cell's natural process to deconstruct that protein. Now, a research team at Indiana University School of Medicine (IU) has identified such a compound for a new target that has long been considered an "unspeakable drug."
The drug, named HB007, is a small molecule-deconstructing agent of the SUMO1 protein. It inhibits tumour progression in mice with brain, breast, colon and lung cancers, the IU team said in a study published in Science Translational Medicine.
The two authors of the study, Addia Belail and Chunhai "Charlie" Hao, have founded a start-up company called HB Therapeutics to develop the drug and other protein degradation agents as anticancer therapies. Indiana-based Elevate Ventures describes HB as its holding company.
In 2014, Belail and Hao found that the SUMO1 protein determines the cell cycle in the development of glioblastoma. SUMO proteins determine various cellular processes by attaching or disconnecting them from other proteins. For this study, researchers examined 1,596 drug compounds to identify those that could inhibit the coupling of SUMO1 with other proteins.
One drug, CPD1, emerged as the best. In the lab trials, the drug showed a wide anticancer activity against human cell lines from brain, breast, colorectal tumours and non-small cell lung cancer. After perfecting the structure of CDP1, the team designed HB007, which was effective in inhibiting the growth of cancer cells in the trials.
Further analysis showed that both CDP1 and HB007 deconstructed SUMO1. The team also found that HB007 cancels a process by which the signal is given for degradation of SUMO1 and purification of it by the competent cells.
In mouse models, HB007 effectively suppressed the progression of human cancers of the colon, breast and lung. Mice with BRCA mutation breast cancer and colon cancer showed increased survival while in the group taking HB007 compared to the animals in the control group, according to the researchers.
Since most human proteins are considered "drug-independent", getting rid of a problematic target through the degradation of proteins has created a "hot" area for the development of anticancer drugs with investments by pharmaceutical companies in the field of biotechnology involving the degradation of proteins.
As for HB007, its effectiveness as a unique agent in various cancer models "highlights the importance of SUMO1 in the progression of cancer and its pharmacological degradation as a widely effective cancer treatment in preclinical models," the IU researchers noted.
