Nouri Neamati, Ph.D. John G. Searle Professor of Medicinal Chemistry
Areas of primary interest to my laboratory include:
- Synthetic medicinal chemistry, machine learning in drug discovery, structure- and ligand-based drug design
- Cellular and molecular pharmacology
- Preclinical drug development.
Specifically, we are interested in performing in-depth preclinical pharmacology of a series of promising small-molecule compounds that we have recently discovered for the treatment of various cancers. A major focus is in the treatment of hard-to-treat cancers such as pancreatic, brain, and ovarian cancers. During the past six years we have embarked on high-risk high-reward projects to create highly innovative new technologies to further enable translation of our findings towards early stage clinical trials. Additionally, we spent a significant amount of our efforts to build a robust infrastructure in chemistry, biology, chemo-, and bio-informatics. This infrastructure has been and continues to be a great resource for the research community at UM. Below are examples of some of our activities in terms of projects that we were engaged during the past three years.
- Pancreatic Cancer
Pancreatic cancer is the 4th leading cause of cancer deaths in the United States mainly due to lack of an effective treatment. Only 9% of patients live beyond 5 years after diagnosis. Developing compounds that exploit the high basal reactive oxygen species (ROS) levels uniquely present in cancer cells is an innovative and promising approach in drug discovery. Currently, there are no specific ROS-inducing drugs under clinical development. Recently, we discovered novel compounds that target the altered cellular bioenergetics characteristic of cancer cells by inducing ROS. We are designing next-generation drugs that are uniquely active in pancreatic cancer and plan to advance these agents toward IND enabling studies. During the past year we designed and synthesized 150 new compounds and selected one compound for in-depth mechanistic studies in mice.
(PDF) Millard, M.; Gallagher, J. D.; Olenyuk, B. Z.; Neamati, N. A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers. J Med Chem 2013, 56, 9170-79.
(PDF) Kuang, Y.; Sechi, M.; Nurra, S.; Ljungman, M.; Neamati, N. Design and synthesis of novel reactive oxygen species inducers for the treatment of pancreatic ductal adenocarcinoma. J Med Chem 2018, 61, 1576-1594.
- Brain Cancer
Glioblastoma (GBM) is the deadliest cancer. The survival of GBM patients is poor with most patients quickly developing resistance to current therapies echoing a great need for rational approaches to treat the resistant tumors. Protein disulfide isomerase (PDI) has a key role in maintaining cellular homeostasis by mediating oxidative protein folding. Increasing evidence suggests that PDI supports the survival and progression of several cancers and most significantly brain cancer. As such, cancer cells are more vulnerable to PDI inhibition than normal cells, making PDI a new and exciting target to treat brain cancer. Previously, we discovered a class of novel and irreversible PDI inhibitors that selectively bind to PDI and demonstrate significant in vivo efficacy with no apparent systemic toxicity. More recently, we performed a high throughput screen and have identified several nM inhibitors of PDI representing the most potent PDI inhibitors discovered to date. We propose to optimize and characterize these compounds to select clinical leads for the treatment of GBM. During the last year we synthesized 125 new analogues and performed stability of three compounds in liver microsomes. We recently published two manuscripts disclosing some of our findings.
(PDF) Shergalis, A.; Bankhead, A., 3rd; Luesakul, U.; Muangsin, N.; Neamati, N. Current challenges and opportunities in treating glioblastoma. Pharmacol Rev 2018, 70, 412-445.
(PDF) Xu, S.; Liu, Y.; Yang, K.; Wang, H.; Shergalis, A.; Kyani, A.; Bankhead III, A.; Tamura, S.; Yang, S.; Wang, X.; Wang, C.-C.; Rehemtulla, A.; Ljungman, M.; Neamati, N., Inhibition of protein disulfide isomerase in glioblastoma causes marked downregulation of DNA repair and DNA damage response genes. Theranostics 2019, 9, 2282-2298.
(PDF) Liu, Y.; Ji, W.; Shergalis, A.; Xu, J.; Delaney, A. M.; Calcaterra, A.; Pal, A.; Ljungman, M.; Neamati, N.; Rehemtulla, A. Activation of the unfolded protein response via inhibition of protein disulfide isomerase decreases the capacity for DNA repair to sensitize glioblastoma to radiotherapy. Cancer Res 2019, 79, 2923-2932.
- Ovarian Cancer
There is an urgent need to develop and validate new predictive biomarkers and new druggable-targets, and to better understand the mechanisms behind these biomarkers in a diverse population of ovarian cancer patients. This is especially significant in epithelial ovarian cancer (EOC) because it comprises a heterogeneous group of tumors with distinct subtypes having different proposed tissues of origin, diverse genetic landscapes, and respond differently to therapy. gp130 is a hub for cytokine signaling and mediates cancer progression. Recently, we have identified first-in-class, efficacious, safe, and orally active inhibitors of gp130. We are using these agents as molecular probes to understand the mechanistic significance and therapeutic potential of targeting gp130 in ovarian cancer.
We are integrating physiologically relevant small cell number spheroid models with next generation sequencing technologies to identify and assess transcriptional and post-transcriptional regulation in genetic networks that are modified after drug treatment on a genome-wide scale. We plan to study chemosensitivity and chemoresistance of our small-molecules drugs in primary and metastatic ovarian cancer spheroids generated to identify druggable targets of ovarian cancer cell metabolism.
(PDF) Xu, S.; Butkevich, A. N.; Yamada, R.; Zhou, Y.; Debnath, B.; Duncan, R.; Zandi, E.; Petasis, N. A.; Neamati, N. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment. Proc Natl Acad Sci U S A 2012, 109, 16348-16353.
(PDF) Xu, S.; Grande, F.; Garofalo, A.; Neamati, N. Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer. Mol Cancer Ther. 2013, 12, 937-949.
(PDF) Lu, T.; Bankhead, A., 3rd; Ljungman, M.; Neamati, N., Multi-omics profiling reveals key signaling pathways in ovarian cancer controlled by STAT3. Theranostics 2019, 9 (19), 5478-5496.