Antitumor Activity of CUDC-305, a Novel Oral HSP90 Inhibitor, in Solid and Hematological Tumor Xenograft Models
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1 Antitumor Activity of CUDC-5, a Novel Oral HSP Inhibitor, in Solid and Hematological Tumor Xenograft Models Rudi Bao, MD/PhD April 1, 2 AACR 1th Annual Meeting 2 Experimental and Molecular Therapeutics 11, Abstract# 2
2 Introduction HSP regulates the folding and degradation of key signaling molecules (client proteins) involved in cancer HSP is upregulated in certain cancers HSP chaperone complexes in cancer have higher affinity to HS inhibitors than those in normal cells; therefore, cancer cells are more sensitive to HSP inhibition HSP inhibitors displays promising antitumor activity in early clinical trials Limitations of the 17-AAG class: poor solubility, potential liver toxicity, substrate for MDR, and limited oral bioavailability Curis aims to develop novel HSP inhibitor that combine the desired attributes of the leading small molecules 2
3 Materials and Methods Structure-based rational design with extensive SAR was utilized to create novel class of HSP inhibitors Binding affinity to HSPα/βwas assessed by fluorescence polarization competition binding assay Anti-proliferation in human cancer cell lines was evaluated with an ATP-based assay PK/PD study was conducted in tumor-bearing mice and samples were analyzed with LC-MS/MS, Western blot, or immunohistochemistry Efficacy studies were conducted in various subcutaneous or orthotopic tumor xenograft models
4 CUDC-5 is a Novel HSP Inhibitor of the Imidazopyridine Class NH 2 R N N N S R2 R1 imidazopyridine class Binding affinity* to HSP of various sources HSP source HSP-α HSP-β Cancer HSP IC5 (nm) *Fluorescence polarization competition binding assay 4
5 CUDC-5 Displays Potent Anti-proliferation Effects in Solid and Hematologic Human Cancer Cell Lines NSCLC Glioblastoma Hepatoma Gastric Colon Breast Ovarian Meso Pancreatic Prostate Renal Sarcoma Melanoma AML CTCL NHL Myeloma Solid tumors Hematologic The median IC5 = 22 nm (range 4 to nm) All IC 5s are well below concentrations achieved in tumor tissue in mouse xenograft efficacy models (~4 to 2 um) 5
6 CUDC-5 Inhibits Oncoproteins, and Downstream Key Signaling Molecules of the Pik/AKT and MAPK Pathways Ctrl CU-4 CUDC-5 Ctrl CU-4 CUDC-5 p-met HSP7 Met H1 P-Flt- ER-α BT474 Flt- Stat5 Mv4-11 AR PSA Ack-1 LnCap p-b-raf A75 Breast Lung Gastric Glioblastoma BT-474 Sk-Br- H1 N-87 M5K LN18 Control CU-4 CUDC-5 Control CU-4 CUDC-5 Control CU-4 CUDC-5 Control CU-4 CUDC-5 Control CU-4 CUDC-5 Control CU-4 CUDC-5 p-akt Akt p-mapk MAPK
7 CUDC-5 Durably Inhibits Oncoproteins, and Downstream Signaling of the Pik/AKT and MAPK Pathways In Vitro Drug treatment Wash and replace medium 7 hrs 17 hrs 24 hrs p-met 7+ hrs 7+17 hrs 7+24 hrs 7+ hrs 7+17 hrs 7+24 hrs MET p-egfr p-akt EGFR AKT p-akt p-erk AKT ERK1/2 C T C T C T H1 C T C T C T H175 7
8 CUDC-5 Displays an Unique PK Profile and Induces Degradation of Multiple Oncoproteins in Tumor Xenografts Single dose PK at mg/kg Single dose PD at 1 mg/kg (U87MG) 1. F=% CUDC-5 1mg/kg PO Control hr hr 24hr 48hr Concentration(uM) Plasma Tumor Brain Lung Liver HSP7 p-akt AKT craf Hours after compound administration Tissue Half life (hour) Cmax(µM) AUC(µmol/L*hour) Plasma C-MET Cleaved PARP Tumor Lung Brain
9 CUDC-5 Inhibits Oncoproteins, Inhibits SubQ Tumor Growth, Prolongs Survival In Orthotopic Models of H175 CUDC-5 1 mg/kg hr 24 hr HSP7 5 H175 subcutaneous tumor EGFR pakt AKT perk1/2 ERK1/2 CDK4 Cyclin D1 PIK MAPK Proliferation TumorGrowth(%) 25 2 po CUDC-5 8mg/kg CUDC-5 mg/kg CUDC-5 1mg/kg cparp ccaspase Apoptosis Days after treatment Survival (%) H175 orthotopic lung tumor CUDC-5 erlotinib Survival (%) 1 CUDC-5 2 mg/kg CUDC-5 4 mg/kg 8 CUDC-5 8 mg/kg CUDC-5 mg/kg Days after tumor implantation Days after tumor implantation
10 CUDC-5 Inhibits Oncoproteins, Inhibits SubQ Tumor Growth, Prolongs Survival In Orthotopic Models of A54 V eh ic le C U D C -5 1 m g /k g h r 24 h r H SP 7 H ER 2 c-r a f1 p-ak T AK T p-m A P K M A P K G A P D H A54 SC tumor 1 A54 orthotopic lung tumor 5 po qod 1mg/kg po qod CUDC-5 erlotinib TumorGrowth(%) 25 Surivival (%) Days Days after tumor implantation 1
11 CUDC-5 Inhibits Tumor Growth, Inhibits Multiple HSP Client Proteins, Suppresses Cell Proliferation/Angiogenesis in U87MG SubQ Tumor CUDC-5 PO q2d Tumorvolume(mm) 1 8 CUDC-5 4 mg/kg 4mg/kg 8mg/kg 1mg/kg HSP7 CUDC-5 8 mg/kg 7 CUDC-5 1 mg/kg cmet pakt 5 4 AKT Raf CyclinD Day after treatment Control CUDC-5 4 mg/kg CUDC-5 8 mg/kg CUDC-5 1 mg/kg Ki7 CD4 11
12 CUDC-5 Prolongs Animal Survival in Intracranial Tumor Models of U87MG Glioblastoma, and H175 NSCLC H175 NSCLC S u rv iva l(% ) % Survival U87MG Glioblastoma CUDC-5 mg/kg 1 CUDC-5 lapatinib Days after tumor implantation Days after tumor implantation
13 CUDC-5 Inhibits Oncoproteins, Induces Complete Tumor Regression in MV4-11 SubQ Tumors of AML CUDC-5 1 mg/kg PO hr hr hr CUDC-5 mg/kg FLT p-akt STAT5 CUDC-5 1 mg/kg HSP7 Tumor volume (mm ) Days after treatment 25 Tumor volume (mm ) Tumor volume (mm ) 25 2 CUDC-5 1 mg/kg 1 5 CUDC-5 2 mg/kg Days after treatment 2 18 Days after treatment
14 CUDC-5 Enhances Standard-of-care Agents in Various Cancer Models H22 NSCLC H175 NSCLC 45 1 erlotinib 25 mg/kg 5 Tumor volume (mm ) paclitaxel.5 mg/kg 7 Combination CUDC-5 mg/kg CUDC-5 1 mg/kg 8 Tumor volume (mm ) 4 Combination Days after treatment MDA-MB48 Breast Cancer Colo-25 Colorectal Cancer CUDC-5 mg/kg 2 paclitaxel.5 mg/kg CUDC-5 mg/kg Combination 18 2 CPT-11 mg/kg Tumor volume (mm ) Tumor volume (mm ) Days after treatment Combination Days after treatment Days after treatment
15 Conclusions Novel class of small molecule HSP inhibitors HSP affinity potency comparable to other leading synthetic HSP inhibitor Excellent PK properties Favorable oral bioavailability (% in mice) Long half-life (~2 hr) in tumor tissues Highly brain penetrable and highly concentrated in the lung Potent efficacy Complete tumor regression in AML models Tumor regression in mouse models of NSCLC, breast, gastric cancer and glioblastoma Extended survival in orthotopic models of lung cancer, intracranial glioblastoma or brain metastasis models Enhance SOC agents in animal models of various tumor types Favorable safety profile MTD in mice ~1 mg/kg, q2d administration GLP toxicology completed
16 Acknowledgements Curis, Inc. Oncology Rudi Bao Dagong Wang Hui Qu Ling Yin Brian Zifcak Molecular/cell biology Cheng-Jung Lai Xu Tao Jing Wang Ruzanna Atoyan Maria Samson Jeffrey Forrester MedChem Xiong Cai Hai-Xiao Zhai DMPK Changgeng Qian Guang-Xin Xu Steve DellaRocca Mylissa Borek Development Carmen Pepicelli Mitchell Keegan Crown Biosciences, Inc. Chunping Xu Curis FTE team Please visit: Poster# 48 (A novel tumor-specific HSP inhibitor with long lasting biological activity) Tuesday, April 21, 2, 1: PM 1
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