Discovery and Optimization of Inhibitors of AAA ATPase p97
p97 modulates protein processes related to protein homeostasis in cancer. It is involved in proteasome-dependent and -independent processes. p97 is required for key pathways that account for clinical efficacy of proteasome inhibitors NF-kB and ERAD but is only required for degradation of a relatively small fraction of proteasome substrates. It may therefore be possible to impact the cancer-relevant UPS functions with good tolerability.
UCSF, UCLA, Caltech
Artemis is a nuclease that is critical for the major pathway of double-strand break repair. It is essential for the successful V(D)J recombination in lymphocytes, and it is a particularly valuable therapeutic target for human acute lymphoblastic lymphoma and leukemia. Its activities are also critical for the resection of damaged DNA overhangs generated by etoposide and X-rays.
Sanford-Burnham, Southern Research, SRI-International, USC
ATG4b is a cysteine protease that activates the autophagy-signaling protein LC3 and also cleaves LC3 from lipids; hence, inhibition of ATG4b is expected to halt autophagy and may induce cell death via protein stress. Protein chemistry and structure analysis suggest a mechanism for LC3 binding to ATG4b, providing a new avenue for the discovery of small molecule inhibitors.
Sanford-Burnham Prebys, UCSF
Discovery and Optimization of Inhibitors of STAT3 Activation
The goal of this project is to develop a therapeutic for head and neck squamous cell cancer that acts as an inhibitor of the STAT3 (signal transducer and activator of transcription 3) signaling pathway. STAT3 is a transcription factor that is constitutively activated in several human cancers. Activation of the STAT3 is stimulated by cytokine or growth factor receptors such as IL-6, which leads to phosphorylation of STAT3 by Janus family kinases (JAKs) on a tyrosine residue. Phosphorylated STAT3 moves from the cytosol to the cytoplasm where it undergoes dimerization followed by translocation to the nucleus, where it binds with DNA to initiate transcription of oncogenic genes including Bcl-2, Bcl-xL, Mcl-1, cyclin D1, c-Myc, MMP-2, and VEGF. It is postulated that an inhibitor of the STAT3 pathway could disrupt oncogenic gene expression and therefore act as a therapeutic for a variety of human cancers, including head and neck squamous cell cancer.
Pittsburgh Specialized Application Center, University of Pittsburgh Drug Discovery Institute, the Grandis group
c-Myc (Myc) is a transcription factor which has been found to be over-expressed and deregulated in many human cancers. Deregulation of the c-Myc oncoprotein leads to gene overexpression and abnormalities of cell growth, survival, differentiation and chromosomal stability. Several of these effects were first described in the work of our collaborator, Ed Prochownik, MD PhD.
Pittsburgh Specialized Application Center, the Prochownik group, Emory Chemical Biology Consortium