Development of inhibitors of the SGK1 kinase, a critical target in anaplastic thyroid cancer

摘要

ABSTRACT This Administrative Supplement is for Aim 2-1: Synthesize sufficient compound quantities to support xenograft studies. Our aims remain within the same scope of our original proposal. Unexpectedly, we found that adding a chiral center confers a great profile on our leads versus non chiral compounds. We showed that chiral leads are selective for SGK1 versus AKT1 (20-fold), active in cells (<100 nM – 20-fold better than other SGK1 inhibitors), have good ADME & PK and no recognized safety issues. FDA guidelines require any IND drug derived from our leads to be chirally pure. At present, materials, labor, and purification of our chiral leads is substantially more expensive than of their nonchiral cousins. In the future, these costs may be reduced via chemical methods development studies, however such studies are beyond the scope of our proposal. As such, our original budget is insufficient to prepare compound for efficacy studies (Aim 2-1). Thyroid cancer is the most rapidly increasing cancer in the United States and it is now the fifth most prevalent cancer in women. Although most thyroid cancers are curable, a subset (~2-5% in the United States and up to 15% worldwide) is invariably fatal. Because these aggressive thyroid cancers lack effective therapies, they account for 40-50% of total thyroid cancer deaths. Genetic, immunohistochemical, epigenetic and animal model studies show that activation of the PI3K/AKT pathway is a pivotal event as thyroid tumors progress from low grade to aggressive subtypes such as anaplastic thyroid cancer (ATC). We have recently provided compelling in vitro and in vivo evidence that the loss or inhibition of the PI3K effector serum and glucocorticoid- regulated kinase 1 (SGK1) profoundly impacts thyroid cancer cell proliferation and survival, despite intact PI3K and AKT activity. This indicates that SGK1 is an integral and essential part of the PI3K transforming machinery and thus represents a novel therapeutic target for ATC. In Phase I, we optimized leads for this historically difficult target. The chiral leads identified have exceptional antiproliferative and pNDRG1 biomarker activities (73 nM, Cpd 613), a value 20-fold more potent than other known SGK1 inhibitors. An Administrative Supplement will allow us to produce chiral compounds need to show proof-of-concept efficacy in an in vivo model of ATC. Once made, our best lead will be tested in a xenograft model of ATC at Albert Einstein College of Medicine in the laboratory of our collaborator, Dr. Antonio Di Cristofano, a recognized leader in thyroid cancer research Successful completion of the Phase I SBIR milestones will justify in vivo optimization and preclinical development of the lead series in Phase II SBIR studies with the goal of treating ATC and poorly differentiated thyroid cancer (PDTC), a thyroid cancer variant that shares many features with ATC. Finally, safety, pharmacology and toxicology profiles will be used in Phase II to select a candidate for IND-enabling studies.