PARP modulators(Poly (ADP-Ribose) polymerase modulators), PTEN modulators(Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN modulators)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication-

Inactive Indication

Endometrial Carcinoma

Originator Organization

The Institute of Cancer Research: Royal Cancer Hospital

KuDOS Pharmaceuticals Ltd.

Active Organization-

Inactive Organization

The Institute of Cancer Research: Royal Cancer Hospital

KuDOS Pharmaceuticals Ltd.

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC21H21FN4O2

InChIKeyHGEPGGJUGUMFHT-UHFFFAOYSA-N

CAS Registry763111-49-5

100 Clinical Results associated with KU-0058948

100 Translational Medicine associated with KU-0058948

100 Patents (Medical) associated with KU-0058948

Literatures (Medical) associated with KU-0058948

01 Dec 2012·Clinical Cancer ResearchQ1 · MEDICINE

Genetically Defined Subsets of Human Pancreatic Cancer Show Unique In Vitro Chemosensitivity

Q1 · MEDICINE

Article

Author: Kenneth W. Kinzler ; Anirban Maitra ; Amanda L. Blackford ; Christine A. Iacobuzio-Donahue ; Surojit Sur ; Yunfeng Cui ; Jacqueline A. Brosnan ; Ralph H. Hruban ; Bert Vogelstein ; James R. Eshleman ; Luis A. Diaz

AbstractPurpose: Pancreatic cancer is the fourth cause of death from cancer in the western world. Majority of patients present with advanced unresectable disease responding poorly to most chemotherapeutic agents. Chemotherapy for pancreatic cancer might be improved by adjusting it to individual genetic profiles. We attempt to identify genetic predictors of chemosensitivity to broad classes of anticancer drugs.Experimental Design: Using a panel of genetically defined human pancreatic cancer cell lines, we tested gemcitabine (antimetabolite), docetaxel (antimicrotubule), mitomycin C (MMC; alkylating), irinotecan (topoisomerase I inhibitor), cisplatin (crosslinking), KU0058948 (Parp1 inhibitor), triptolide (terpenoid drug), and artemisinin (control).Results: All pancreatic cancer cell lines were sensitive to triptolide and docetaxel. Most pancreatic cancer cells were also sensitive to gemcitabine and MMC. The vast majority of pancreatic cancer cell lines were insensitive to cisplatin, irinotecan, and a Parp1 inhibitor. However, individual cell lines were often sensitive to these compounds in unique ways. We found that DPC4/SMAD4 inactivation sensitized pancreatic cancer cells to cisplatin and irinotecan by 2- to 4-fold, but they were modestly less sensitive to gemcitabine. Pancreatic cancer cells were all sensitive to triptolide and 18% were sensitive to the Parp1 inhibitor. P16/CDKN2A-inactivated pancreatic cancer cells were 3- to 4-fold less sensitive to gemcitabine and MMC.Conclusions: Chemosensitivity of pancreatic cancer cells correlated with some specific genetic profiles. These results support the hypothesis that genetic subsets of pancreatic cancer exist, and these genetic backgrounds may permit one to personalize the chemotherapy of pancreatic cancer in the future. Further work will need to confirm these responses and determine their magnitude in vivo. Clin Cancer Res; 18(23); 6519–30. ©2012 AACR.

14 May 2009·Journal of Medicinal ChemistryQ1 · MEDICINE

Structural Basis for Inhibitor Specificity in Human Poly(ADP-ribose) Polymerase-3

Q1 · MEDICINE

Article

Author: Weigelt, Johan ; Schüler, Herwig ; Jemth, Ann-Sofie ; Holmberg-Schiavone, Lovisa ; Hammarström, Martin ; Collins, Ruairi ; Karlberg, Tobias ; Loseva, Olga ; Johansson, Andreas ; Flores, Alex ; Helleday, Thomas ; Lehtiö, Lari ; Markova, Natalia

Poly(ADP-ribose) polymerases (PARPs) activate DNA repair mechanisms upon stress- and cytotoxin-induced DNA damage, and inhibition of PARP activity is a lead in cancer drug therapy. We present a structural and functional analysis of the PARP domain of human PARP-3 in complex with several inhibitors. Of these, KU0058948 is the strongest inhibitor of PARP-3 activity. The presented crystal structures highlight key features for potent inhibitor binding and suggest routes for creating isoenzyme-specific PARP inhibitors.

01 May 2009·HaematologicaQ1 · MEDICINE

Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes

Q1 · MEDICINE

Article

Author: Sydney Shall ; Natalie A. Twine ; Nicholas C. Lea ; Farzin Farzaneh ; Lee J. MacPherson ; Terry J. Gaymes ; Ghulam J. Mufti

Background Aberrant or impaired repair of double-strand DNA breaks is a common feature of de novo acute myeloid leukemia and myelodysplastic syndromes. Since poly (ADP-ribose) polymerase (PARP) inhibitors have been recently shown to selectively target cells with defects in double-strand DNA repair, the aim of this study was to explore the possibility of exploiting defects in DNA repair in leukemic cells using PARP inhibitors.DESIGN AND METHODSLeukemic cell lines were exposed to various PARP inhibitors alone and in combination with non-cytotoxic concentrations of DNA methyltransferase inhibitor, 5' aza-2'-deoxycytidine and/or the histone deacetylase inhibitor, MS275, to test for potentiation of apoptosis with these agents.RESULTSPARP inhibitors, KU-0058948 and PJ34, induced cell cycle arrest and apoptosis of primary myeloid leukemic cells and myeloid leukemic cell lines in vitro. Immunofluorescence analysis also revealed that PARP inhibitor sensitivity in these leukemic cells was due to a defect in homologous recombination DNA repair. Addition of 5' aza-2'-deoxycytidine failed to increase the cytotoxicity of PARP inhibitors. In contrast, MS275 potentiated the cytotoxic effect of KU-0058948 and PJ34 in all PARP inhibitor-sensitive leukemic cells. Immunofluorescence analysis supported the idea that histone deacetylase inhibitors potentiate cytotoxicity by inhibiting DNA repair processes. Conclusions On the basis of the data presented here, we suggest that PARP inhibitors can potentially exploit defects in double-strand DNA break repair in leukemic cells, paving the way for testing the therapeutic potential of these agents in myelodysplastic syndromes and acute myeloid leukemia.

100 Deals associated with KU-0058948

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Indication	Highest Phase	Country/Location	Organization	Date
Endometrial Carcinoma	Preclinical	GB	The Institute of Cancer Research: Royal Cancer Hospital	12 Oct 2010

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