A Central Role for Biophysics in Cancer Drug Discovery - Development of Candidate Small Molecule Inhibitors in Mutant KRas

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The Ras GTPase family is comprised of three proto-oncogenes (HRas, KRas and NRas) cycling between inactive GDP and active GTP bound states. Active KRas localises to the plasma membrane and signals through a functionally diverse set of down-stream effector proteins (including RAF1) to influence cellular differentiation, growth, survival and apoptosis. Mutant KRas, which is ostensibly stabilised in the active GTP form, is well validated and linked to over 20% of human cancers, making it a highly desirable target in oncology drug discovery. We have employed a combination of biophysical techniques as central drivers for drug discovery, interacting with medicinal chemistry to establish structure-activity relationships (SAR), increasing affinities and improving the binding kinetics of candidate small molecules targeting mutant KRas. Fragment based screens using surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) yielded a number of different chemical starting points. These initial hits, which exhibited high millimolar affinities, have evolved and grown to deliver a set of molecules that exhibit submicromolar affinity with additional help of crystallography, isothermal titration calorimetry (ITC) and computational modelling. The improved binding is also translating to functional effects in vitro in additional biochemical assays. This study demonstrates the impact of Biophysics in a critical area of cancer drug discovery and how its interplay with medicinal chemistry has developed promising compounds that aim to interrupt KRas signalling and thus decrease KRas dependent oncogenesis.