靶向治疗透明细胞肾细胞癌中的铁凋亡：将KCRP的研究成果转化为临床应用.pdf

1、Inducing Ferroptosis in ccRCC:Translating KCRP Discoveries to the ClinicMei Yee Koh,PhDAssociate Professor,University of UtahFounder and CEO,Kuda Therapeutics,IncDisclosure:I own stock and receive remuneration from Kuda Therapeutics,Inc Ferroptosis Exploits ccRCC Vulnerabilities Three Features of Fe

2、rroptosisPUFA-PLsRedox-active IronDefective lipid peroxide repair Ferroptosis is a form of cell death in which lipid oxidation,catalyzed by excess iron,destroys cells through a chemical chain reaction typical cancer resistance mechanisms may be irrelevant HIF-1/2 in ccRCC enriches for polyunsaturate

3、d fatty acid containing phospholipids(PUFA-PLs)ccRCC have 20 x more iron than uninvolved kidney Increased PUFA-PLs and iron drive sensitivity to ferroptosishttps:/news.columbia.edu/news/10-years-cell-death-discovery-shows-promise-treating-diseaseArtistic rendering ferroptosis as a wildfireDevelopmen

4、t TimelineEXCLUSIN ZONE360,000 compounds screened for HIF-2 inhibition62 validated actives across 5 chemical scaffoldsLead scaffold identifiedNIH/NIDA screening grant(2012-2014):uHTS screenLead IDNIH/NCI SBIR Phase I grant(2018-2020):$300KKD025NIH/NCI SBIR Phase II grant(2022-2025):$2Mnon-GMP manufa

5、cture,ADME,Tox DoD PRMRP Therapeutics Dev Award(2025-2028):$5.6MKD061 IND FilingGLP Tox,cGMP manufactureDoD KCRP Award(2020-2023):$560KLead optimizationKD061Molecular Mechanism of Action KD061 inhibits Iron-Sulfur Cluster Assembly 2(ISCA2),a protein involved in iron utilization Inhibition of ISCA2 c

6、reates a perception of iron starvation in cells-stimulates iron uptake and blocks HIF synthesis ccRCC have increased iron compared to normal tissue enables tumor selectivity for KD061-induced ferroptosisROS:Reactive oxygen species;IRE:Iron-