NYU001

Dr. Ann-Marie Schmidt is an internationally acclaimed investigator in the biology of diabetes and its vascular complications. The receptor for advanced glycation end products (RAGE) is a cell-surface receptor, originally discovered by Dr. Schmidt, which has been implicated in a variety of diseases, most notably development of diabetes and diabetic micro- and macro-vascular complications such as diabetes-associated nephropathy, neuropathy, retinopathy and atherosclerosis. Many attempts to drug RAGE extra-cellularly have failed namely due to the large redundancy in ligand activation of RAGE.

We identified a key intracellular interaction in the RAGE pathway involving its partner mDia1. After screening for inhibitors of this interaction, we identified 14 hits that biochemical, cellular and animal RAGE-specific assays prioritized them into two chemical series and a handful of singletons. We are currently optimizing the hits for better potency, drug properties and novelty. 

NYU007

There are numerous demyelinating diseases such as MS, cerebral palsy and many rare diseases that could benefit from novel remyelinating drugs. Notably, in MS, while there are many drugs approved or in development, the vast majority target inflammation, and not repairing damaged myelin.

Dr. James Salzer, Professor of Neurology and Cell Biology, is a major investigator in myelination processes and has identified an important and unexpected mechanism for repairing myelin damage. His work has uncovered that Gli1, a transcription factor in the SHH pathway, inhibits recruitment of stem cells to sites of myelin damage. In animal models of demyelination, inhibition of Gli1 both genetically and using a small molecule Gli1 tool compound increases recruitment of stem cells and myelin repair. We are currently optimizing the tool compound for better potency, drug properties and novelty, as well identifying additional targets in this pathway. 

NYU009

Dr. William Carroll has identified an interesting drug target for relapsing leukemia, NT5C2, where patient samples led us to identify gain of function mutations in this enzyme driving resistance to a certain class of first-line chemotherapy (with a somewhat clear mechanism of action). Additionally, we have many tools and collaborators focused on NT5C2 enzymology, animal models and clinical samples. We are initializing assay development for high throughput screening to identify inhibitors selective for mutant NT5C2. 

NYU011

There are several drugs targeting CRPC in development but there remain opportunities for drugs that are superior or complementary to new agents such as ARN-509 and enzalutamide. Drs. Kent Kirshenbaum and Michael Garabedianare developing novel multivalent agents that increase the avidity of inhibiting the androgen receptor (AR). This novel approach aims to counter drug resistance mechanisms typically observed with AR. Our agents potently and selectively inhibit proliferation of castrate-resistant prostate cancer cell lines in vitro and in vivo, and show favorable DMPK profiles. We have data showing superior efficacy of our compounds over enzalutamide in inhibiting proliferation of castrate resistant cell lines. We are currently optimizing our agents for better potency and drug properties. 

NYU013

Excessive bone destruction can be caused by enhanced osteoclast activity, including implant particle-induced inflammation resulting in prosthetic loosening and replacement as well as rheumatoid and psoriatic arthritis. Additionally, osetolysis is a common complication of bone metastases in cancers such as prostate cancer, breast cancer and multiple myeloma.

Dr. Bruce Cronstein and Dr. Kathryn Moore have identified Netrin-1, a secreted protein, as an attractive drug target for osteolytic diseases. Transgenic mice lacking netrin-1 have increased bone volume and density linked to a significantly reduced osteoclast population. Additionally, blockade of Netrin-1 and its receptor inhibits osteoclast differentiation and function. Further target validation studies using animal models of particle induced osteolysis reveals high expression of Netrin-1 in inflammatory infiltrates which is also observed in human patient samples undergoing revision surgery for implant osteolysis and loosening.

In partnership with MRCT, we are co-developing efficacious and safe biologics targeting Netrin-1 for the osteolysis market.