 Tolias, Peter |
Academic Appointments: Dean, School of Natural and Behavioral Sciences, Brooklyn College, The City University of New York Degree Research Focus: My research team has focused on understanding the biochemistry of the Mitogen Activated Protein Kinase (MAPK) Signaling pathway and its role in cancer by developing and using drugs that can therapeutically modulate this biochemical pathway. The signaling that occurs within this pathway is extremely important as it controls many essential cellular functions such as cytoskeleton organization, aging and programed cell death, calcium signaling, trafficking of vesicles, and cellular proliferation/cell division. Proliferation of cells is a critical component of the MAPK pathway because when perturbed leads to many different types of solid tumors as well as blood cancers. To date, only two proteins, BRAF and MEK. that function in the MAPK pathway have been successful targeted with available FDA approved drugs. The problem with all currently approved drugs against these two targets is that patients develop resistance to the therapeutic effects of these drugs within two years and the caner returns, hence the need to develop new drugs against other targets in the MAPK pathway. At the top of the MAPK pathway are the products of the RAS gene which are among the highest priority drug targets in oncology. This gene is mutated, causing it to be hyperactive, in 30% of all human tumors including 90% of pancreatic, 45% of colon and 35% of lung cancers. Cancers with KRAS mutations are aggressive and respond poorly to standard untargeted chemotherapies. We have used computational modeling (supercomputing) of the mutated KRAS protein based on published X-ray crystallography data to determine areas that a drug can possibly bind as well as computational chemistry of compounds developed by others that have failed to effectively modulate the pathway. This metanalysis has led us to many new ideas of how to develop new candidate compounds. We then used medicinal organic chemistry to develop these new drug candidates against KRAS and proceeded to accesses them in biochemical assays. After numerous failures, a compound was synthesized with low but reproducible (in triplicate) biochemical inhibition (12%) of the hyperactive KRAS G12C mutant. We have also designed and synthesized a novel analogue of this compound in an effort to significantly enhance its potency. Computational modeling (supercomputing) of the mutated KRAS protein was also used based on published X-ray crystallography data to determine areas that a drug can possibly bind as well as computational chemistry of compounds developed by others that have failed to effectively modulate the pathway. This metanalysis has led us to many new ideas of how to develop new candidate compounds. We then used medicinal organic chemistry to develop these new drug candidates against KRAS and proceeded to accesses them in biochemical assays. After numerous failures, a compound was synthesized with low but reproducible (in triplicate) biochemical inhibition (12%) of the hyperactive KRAS G12C mutant. We have also designed and synthesized a novel analogue of this compound in an effort to significantly enhance its potency. A second target that we have pursued is the SOS protein which physically interacts with RAS and controls it’s GTPase activity and subsequent signaling. We studied the 3D X-ray structure of this interaction from publicly available data banks and identified a contact point that had a groove in SOS that we believed may offer a new target site to develop compounds that would inhibit the interaction in biochemical assays. We then proceeded to use computational modeling on a supercomputer and identified theoretical compounds that fit in this groove out of 11 million possible structures using high throughput docking at this junction site. Three of these compounds (out of the 103 that were identified by computational modeling) were confirmed biochemically with low micromolar potency and share a common scaffold. We are currently designing and synthesizing novel analogues of these compounds to significantly enhance their potency. Our third target in the MAPK pathway is ERK which is the last key protein involved in the signaling cascade. A drug against ERK would create a new effective first line treatment for melanoma, colon and pancreatic cancer and new hope for patients with BRAF and MEK resistant tumors. We have spent most of our effort on this target and have been able to push our progress to a significant milestone. Our approach was similar to what was done in the RAS project described earlier in that we used computational modeling (supercomputing) of the ERK protein based on published X-ray crystallography data to determine areas that a drug can possibly bind as well as computational chemistry of compounds developed by others that have failed to effectively modulate the pathway. We then used medicinal chemistry in an attempt to develop a novel, potent, selective, orally efficacious ERK inhibitor. Fortuitously, one of the candidate compounds that we synthesized early in our efforts was able to inhibit ERK in a biochemical assay with excellent potency. Through multiple cycles of computational refinement, organic chemistry synthesis and biochemical assessment, we have identified a very potent compound in the low nanomolar range Selected Publications
Patents
Grants over the last 5 years
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