Development of a novel class of selective HIF-2A inhibitors for kidney cancer

Abstract Clear cell type renal cell carcinomaCRCCthe most prevalent form of kidney canceris among the most resistant of tumors to traditional chemotherapy and radiationIt has become established that CRCC is uniquely driven by the hypoxia inducible factorHIFwhereas the closely related HIFplays a tumor suppressor roleand is frequently deleted in advanced tumorsSince HIFis rarely detected in normalwell perfused tissuethe selective inhibition of HIFis an attractive therapeutic strategy for CRCCThrough a high throughput screening campaignKuda Therapeutics has identified a series of compounds that specifically decrease HIFprotein without affecting HIFThis provides a dual and profound benefit by inhibiting both the transcriptional and non transcriptional targets of HIFThe compounds act by enhancing the binding of iron regulatory proteinIRPto the iron responsive elementIREwithin theuntranslated region of HIFmRNAwhich blocks HIFtranslationMultiple rounds of structure activity relationshipSARanalysis have identified a lead chemotype of which Kis the most potentwith HIFICMKtreatment inhibits the growth of CRCC xenografts in miceand decreases the levels of HIFwithin the tumorAdditionallyplasma ferritinwhich also contains aIREserves as a pharmacodynamicPDbiomarker for KKis well tolerated in mice with no detectable signs of toxicityincluding liver or kidney toxicityafterdays of continued dosing atmg kgWe aim to show that this novel strategy for the selective depletion of HIFprotein will provide benefit to patients with CRCCOur goal is to produce a noveli epatentableseries of related compounds with improved potency and desirable in vivo characteristics to assess the feasibility and commercial potential of this therapeutic approachOur first aim is to synthesize novel derivatives of our lead series for in vitro characterization through multiple rounds of iterative SARThese will be based on our initial HTS and predicted to have improved in vivo characteristicsCompounds will be subjected to in vitro HIFactivity screensas well as preliminary in vitro ADME Tox studiesPromising compounds from this aim will be channeled to Aimfor in vivo characterization including additional PK PD studiesCRCC anti tumor studiesand further toxicity metabolic characterization for the most promising compoundAt the end of the projectwe will have identified at least one novel compound with enhanced anti tumor activity and biomarker validationwith preliminary toxicity analysis to facilitate transition to Phase II Project Narrative Kidney cancer is among the most drug resistant of solid tumorsand is uniquely dependent upon HIFfor its continued growth and progressionWe have identified a molecule that specifically blocks HIFproduction and slows tumor growth in miceOur studies will improve this molecule in order to facilitate its commercial development as a new medicine for the treatment of kidney cancer