TITLE:
Prospective Development of Small Molecule Targets to Oncogenic Ras Proteins
AUTHORS:
Reena Chandrashekar, Paul D. Adams
KEYWORDS:
Ras [Rat Sarcoma]; Small Molecule Target; Structure-Based Drug Design; Fragment-Based Drug Design; GTP Hydrolysis; Guanine Nucleotide Exchange Factors [GEF]
JOURNAL NAME:
Open Journal of Biophysics,
Vol.3 No.4,
October
15,
2013
ABSTRACT:
Abnormal expression or mutations in Ras
proteins has been found in up
to 30% of cancer cell types, making them excellent protein models to probe
structure-function relationships of cell-signaling processes that mediate cell
transformtion. Yet, there has been very little development of therapies to help
tackle Ras-related diseased states. The development of small molecules to
target Ras proteins to potentially inhibit abnormal Ras-stimulated cell
signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies
characterizing Ras protein-small molecule interactions to show the importance
and potential that these small molecules may have for Ras-related drug discovery.
We summarize recent results, highlighting small molecules that can be
directly targeted to Ras using Structure-Based Drug Design (SBDD) and
Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic
signaling in vitro by small molecules
is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this
regard, important features of previously characterized properties of small molecule Ras targets, as well as a current
understanding of conformational and dynamics changes seen for Ras-related mutants,
relative to wild type, must be taken into account as newer small molecule
design strategies towards Ras are developed.