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Our programs are focused on the development of new generations of agents for the treatment of Alzheimer's disease and various forms of cancer.
Our scientists have clearly demonstrated that phosphatidylinositol-4,5-bisphosphate (PIP2) modulates the levels of the 42-residue amyloid β-peptide (Aβ42), which is strongly implicated in AD pathogenesis. Proof-of-concept has been demonstrated using SMT-3, a small molecule phosphoinositide (PI) synthesis modulator, which not only selectively lowers Aβ42 [γ-secretase modulating (GSM) activity], but also inhibits the synaptic dysfunction induced by toxic oligomeric forms of Aβ42. SMT-3 has been shown to improve behavior and memory when evaluated in transgenic mouse models of Alzheimer's disease.
Current R&D activities are focused on:
- Using SMT-3 as a structural lead to identify improved molecules with clear worldwide patent exclusivity.
- Developing novel clauses of small-molecule modulators of PI-specific lipid kinases and phosphatases, that mimic both GSM activity and inhibition of the synaptic dysfunction caused by oligomeric forms of Aβ42.
SMART's ongoing oncology discovery and development program is focused on selective inhibitors of HAUSP (Herpes-associated ubiquitin-specific protease, USP7), a novel p53-interacting protein, as well as inhibitors of ARF-BP1, a novel-binding molecule of the ARF tumor suppressor. Loss of p53 function is strongly implicated in cancer development, as mutations in the p53 gene and other defects in the p53 pathway are observed commonly in tumor cells. p53 abundance and activity are tightly regulated through rapid degradation (ubiquitination) by the enzyme Mdm2/Hdm2, which also undergoes self-degradation. HAUSP has been shown to prevent the self-degradation of Mdm2/Hdm2, thereby increasing the availability of Mdm2/Hdm2 to degrade p53. Inhibition of HAUSP, in turn promotes the self-degradation of Mdm2/Hdm2, leading to stabilization of p53 and induction of p53-mediated tumor-cell death (apoptosis).
Recent data from the laboratory of Dr. Wei Gu at Columbia, demonstrated that ARF-BP1 promotes tumor formation via both p53-dependent and independent mechanisms. Thus, an inhibitor of ARF-BP1 should be useful as a next-generation agent for treating a variety of tumor types, including those not responsive to currently available anti-tumor agents and treatment regimens.
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