Geoff Miller

Graduate Student

Department of Pharmaceutics & Pharmaceutical Chemistry

30 S 2000 E
LS Skaggs Pharmacy Institute
Salt Lake City, Utah, 84112
USA
ph: 801.581.7120

miller.geoffrey3@gmail.com

Research Project

95% of CML cases are characterized by the presence of a reciprocal translocation between the c-ABL portion on chromosome 9 and the breakpoint cluster region (Bcr) on chromosome 22, forming what is known as the Philadelphia chromosome.  The gene product stemming from this chromosome, Bcr-Abl, functions in these cells as a constitutively active tyrosine kinase which activates cell proliferative pathways.  For Bcr-Abl to function in this manner, it must homo-oligomerize through a coiled coil domain, as the resulting dimer-of-dimers allows for the constitutively active kinase activity.  Previous research in the Lim Lab has shown that the disruption of this homo-oligomerization can prevent the characteristic kinase activity, thus upregulating apoptotic activity in the cells.

 

My project focuses on rationally designed coiled coil mutants (designated CCmut) as a potential therapeutic to eliminate CML cells.  Andy Dixon’s work in our lab has shown these compounds can bind to endogenous Bcr-Abl and disrupt the oligomerization necessary for proliferation of CML cells.  I am currently working with Andy on a “second generation” CCmut in conjunction with Dr. Tom Cheatham (in Medicinal Chemistry), which appears to have stronger binding to Bcr-Abl in vitro.  While strong binding to full length Bcr-Abl and apoptotic activity have been shown for these CCmuts, their size at ~8.8 kDa (amino acids 1-72) remains on the larger side for an easy-to-administer therapeutic.   Therefore, I will determine the smallest possible molecule that can be used to provide the same effect.  Specifically, I plan to examine and test the feasibility of just using the second of two alpha-helices (helix-2, amino acids 23-72) from the full-length coiled coil domain as a smaller therapeutic agent.  Mutations in the previous CCmut can be maintained in helix 2; other additional mutations or “capping” of the peptide may be necessary.  The goal is to create a small peptide that can be used to successfully disrupt Bcr-Abl oligomerization allowing the elimination of CML cells.  Eventually, Ben Bruno and I will be working together on the delivery of this peptide using his cell-penetrating peptides.