eIF4A Inhibitors For Drug-resistant Cancers
eIF4A inhibitors for drug-resistant cancers
Seeking investment for the development of lead candidates to clinical PoC
The biggest challenge facing cancer medicine today is that of drug resistance… and this should be the focus of all our activity (BMJ April 2019; P Workman, President ICR)
There is a clear need to find treatments for drug-resistant and refractory cancers and to reduce the risk of relapse. Resistance to classical chemotherapy is responsible for most relapses – one of the major causes of death of the disease – but mechanisms of resistance are becoming ever more challenging. Today, for cancers such as colon, lung, kidney, pancreatic and ovarian, there are few effective treatments and, often, no SoC available. For these cancers, there has been no real movement in survival rates for >40years.
Translation Inhibition (TI) offers an intriguing route to enable effective treatment of resistant & refractory tumours: inhibiting translation prevents protein synthesis of mRNA. Dysregulated translational control is associated with most cancers (as well as other diseases). Aberrant protein synthesis is a widespread characteristic of rapidly dividing tumour cells: it is independent of the genetic make-up of the cancer.
An abundance of translation initiation factors (eIF) is associated with cancer cell proliferation and drug-resistance. eIF4A is at the heart of many different proto-oncogenic pathways, including c-myc and RAS. Many pro-oncogenic signalling pathways converge on cap-dependent translation and these can be inhibited by targeting eIF4A.
eIF4A regulates translation and represents a valuable target for cancer drug development
A research group in the university of Nottingham has developed a series of small molecule eIF4A inhibitors, derived from natural sources, and is developing a lead candidate (AG139) for the treatment of drug-resistant & refractory solid tumours and those prone to relapse.
AG139 is a differentiated, best in class eIF4A inhibitor, with Preclinical PoC for drug-resistant and refractory cancers
In preclinical xenograft models of refractory cancers, where standard chemotherapy agents have no effect, AG139 treatment induces tumour growth inhibition and regression. Anti-tumour effects are consistent regardless of tumour type or genotype.
AG139 impacts metastasis and effects tumour biology in a way that is distinct from chemotherapy. It acts on the high-density metabolic core of tumours, with long-term treatment likely to induce a sustained response.
AG139 reduces key oncogenic proteins that drive angiogenesis within the tumour (eg VEGFR2) and inhibits cell proliferation.
AG139 drives synergy with cancer agents, enabling new treatment options for hard-to-treat cancers that are prone to relapse. However, AG139 also demonstrates monotherapy activity in cancers with no SoC: inhibiting tumour growth in drug-resistant glioblastoma and metastatic prostate cancer xenografts.
AG139 has a conventional PK profile for a small molecule therapeutic – consistently inducing cMax for a broad range of cell lines. It is amenable to oral and IV formulations; it has a low LogP value and is readily soluble in a range of known solvents.
AG139 represents a truly exciting opportunity that could revolutionise treatment of resistant and refractory cancers. We are seeking investment or collaborations to progress AG139 to clinical proof of concept.