Premium
Towards the Identification of the Minimal Pharmacophore of KDT‐11
Author(s) -
McCartney Julia,
Dickson Paige,
Kodadek Thomas
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.531.3
Subject(s) - peptoid , pharmacophore , cytotoxicity , chemistry , bortezomib , small molecule , computational biology , biochemistry , peptide , biology , in vitro , multiple myeloma , immunology
The 26S proteasome is a key player in a number of cell processes that help to remove misfolded and downregulate targeted proteins. Rpn13, a subunit of the 19S regulatory particle of the proteasome, is a ubiquitin receptor and UCH37 recruiter and activator. Rpn13 can be knocked out of yeast and mouse models without the development of a new phenotype, yet in many cancer cells it is over expressed. In 2015, the peptoid KDT‐11 was shown to be highly selective towards Rpn13 and toxic to multiple myeloma cells. However, because of this compound's size and hydrophobicity, it is a poor candidate for further development as a drug. Preliminary lab data suggests that N‐methyl‐N‐(3‐fluorobenzylamine) in the terminal position of the 6‐mer peptoid is critical for selective toxicity. However, the necessity of the amines in all other positions is not known. To make the molecule more biologically viable, I synthesized ten derivatives using solid‐phase bead synthesis. Florescence polarization and cell viability assays were conducted to assess the potential improvement or detriment offered by each variation, using KDT‐11 and Bortezomib, a 20S core particle inhibitor, as control factors. I found that shortening the peptoid does not inherently result in a loss of selectivity or cytotoxicity, and in some cases, appears to lead to an increase. However, truncating past a 4‐mer length resulted in general cytotoxicity to control and cancerous cells. These data indicate that while a certain length must be maintained, only the terminal N‐methyl‐N‐(3‐fluorobenzylamine) is position dependent. This development is highly advantageous as it targets a different subunit of the proteasome than currently available drugs, and could potentially be used in parallel. Support or Funding Information We would like to thank the Scripps Summer Undergratuate Research Fellowship for funding this work This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .