Novel approaches to cancer therapy

Abstract

SoS protein is responsible for keeping Ras, a key molecular switch involved in cell division, turned on. In many cancers a mutation in the Ras protein can permanently lock the molecular switch into the ‘on’ position, leading to enhanced cell division. This problem is especially relevant to pancreatic cancer, which has a particularly high prevalence of mutant Ras driven tumours (90%). Inhibiting the ability of SoS to catalyse nucleotide exchange on Ras has the potential to afford a means of targeting oncogenic Ras signalling. In preliminary studies, we have identified small molecule compounds that bind to an unprecedented site on SoS itself and have the potential to inhibit Ras activation via a novel allosteric mechanism. Currently, we are exploring and modifying the structure of this small molecule to achieve a more potent and drug-like compound. Small-molecule inhibitors of interferon regulatory factor 4 (IRF4) Interferon regulatory factor 4 (IRF4) is a transcription factor that has been shown to regulate the survival of several aggressive lymphoid malignancies. It appears to be a master-regulator of gene transcription in myeloma, influencing cellular survival, proliferation, metabolism and differentiation. siRNA knockdown of IRF4 by only 40 – 60% is lethal to myeloma cells. The possibility of inhibiting IRF4 with drug-like small-molecules could be a useful therapy in a number of aggressive lymphoid cancers. High Throughput Screen using Fluorescence Polarization assay for the IRF4 DNA Binding Domain and a fragment-based screen using SPR and NMR were undertaken. 7 hits were obtained from both screens and 63 close analogues were synthesised to explore SAR and address physicochemical properties. FragLites: Bifunctional Halogenated Fragments Identification of ligand binding sites on proteins is of critical importance for chemical biology and drug discovery applications. We describe an efficient and comprehensive approach to mapping interaction sites on a protein using a designed set of bifunctional halogenated fragments that express hydrogen-bonding pharmacophore doublets. These fragments are capable of seeking out productive polar interactions and can be identified unambiguously by X-ray crystallography by the anomalous scattering of their halogen substituent. Soaking this set of compounds with CDK2 elucidated previously identified binding sites and also new ones, which can be used as starting points for fragment growing and drug designMDM2-PROTACS for the Androgen Receptors (AR) PROTACS (proteolysis targeting chimeric molecules) have been recently disclosed as chemical tools to target specific proteins for destruction by the proteasome. PROTACS comprise a ligand for an E3 ligase protein that may be a peptide or small molecule, and a ligand for the target protein. The advent of highly potent and specific ligands for MDM2 (E3 ligase) offers the opportunity to develop MDM2-PROTACS. Several compounds were designed to target the Androgen Receptor via Flutamide using two different MDM2 ligands and a broad variety of linkers We have demonstrated the activity of MDM2 PROTACS for degradation of the AR and confirmed the importance of the linker length in different in vitro assays. The influence of the potency of the E3 ligase ligand was also confirmed by SPR experiments.