Zeroing in on a protein that has been shown to aid in cancer resistance to current chemotherapies, a Barbara Ann Karmanos Cancer Institute researcher and a University of Michigan collaborator have teamed up to develop a new class of anti-cancer drugs.

Ramzi Mohammad, Ph.D., professor of Oncology for Karmanos and the Wayne State University School of Medicine, and Zaneta Nikolovska-Coleska, Ph.D., assistant professor of Pathology at the University of Michigan, have received two grants from the National Institutes of Health. The grants secure more than five years of funding for both researchers and will help in the development of novel small molecule drugs for highly-resistant solid and liquid tumors. Efficacy of the most promising molecules will be tested in pancreatic cancer.

Resistance to apoptosis, or programmed cell death, is a common problem in the treatment of human malignancies and underlies the observed lack of response to both conventional chemotherapy and approaches that specifically target apoptotic mechanisms.

Drs. Mohammad and Nikolovska-Coleska will investigate potential inhibitors for myeloid cell leukemia-1 (Mcl-1), a member of the Bcl-2 family of proteins which are central regulators of apoptosis. Mcl-1 has been found to be over-expressed in both solid and non-solid tumor cell lines and human cancer tissues. Such over-expression has led to its association with tumor initiation and progression.

Using high throughput screening, Drs. Mohammad and Nikolovska-Coleska have discovered more than 20 small molecules that show promise as Mcl-1 inhibitors. With their first grant, they will perform further chemical modifications to the inhibitors to improve potency, specificity and efficacy in targeting the Mcl-1 protein for the treatment of cancer.

The second grant will be used to optimize the most potent and clinical grade Mcl-1 inhibitor in the treatment of pancreatic adenocarcinoma.

“Well known as having over-expression of Mcl-1, this incurable disease of the pancreas is one of the most suitable targets for these inhibitors,” Dr. Mohammad said.

In the last decade, Dr. Mohammad has worked with different classes of small molecule inhibitors.