PARP1 inhibitors(Poly (ADP-Ribose) polymerase 1 inhibitors), PARP2 inhibitors(Poly (ADP-Ribose) Polymerase 2 inhibitors), PARP6 inhibitors(poly(ADP-ribose) polymerase family member 6 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization-

Active Organization

AstraZeneca PLC

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with AZ0108

100 Translational Medicine associated with AZ0108

100 Patents (Medical) associated with AZ0108

Literatures (Medical) associated with AZ0108

01 Dec 2018·Cancer ResearchQ1 · MEDICINE

Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer

Q1 · MEDICINE

Article

Author: Gharahdaghi, Farzin ; Tate, Edward W. ; Zinda, Michael ; Wang, Wenxian ; Grosskurth, Shaun E. ; Fawell, Stephen E. ; Lawson, Deborah ; Wang, Zebin ; Su, Nancy ; Cheung, Tony ; Lamb, Michelle L. ; Wu, Jiaquan ; Lyne, Paul D. ; Mayo, Michele ; Scott, David A. ; Zhang, Jingwen ; Reimer, Corinne ; Wang, Xin ; Mikule, Keith ; Petteruti, Philip ; Widzowski, Dan ; Howard, Ryan T. ; Dry, Jonathan R. ; Chen, Huawei ; Johannes, Jeffrey W.

AbstractPARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) generating PARP, including PARP6, remain largely uncharacterized. Here, we report a novel therapeutic strategy targeting PARP6 using the first reported PARP6 inhibitors. By screening a collection of PARP compounds for their ability to induce mitotic defects, we uncovered a robust correlation between PARP6 inhibition and induction of multipolar spindle (MPS) formation, which was phenocopied by PARP6 knockdown. Treatment with AZ0108, a PARP6 inhibitor with a favorable pharmacokinetic profile, potently induced the MPS phenotype, leading to apoptosis in a subset of breast cancer cells in vitro and antitumor effects in vivo. In addition, Chk1 was identified as a specific substrate of PARP6 and was further confirmed by enzymatic assays and by mass spectrometry. Furthermore, when modification of Chk1 was inhibited with AZ0108 in breast cancer cells, we observed marked upregulation of p-S345 Chk1 accompanied by defects in mitotic signaling. Together, these results establish proof-of-concept antitumor efficacy through PARP6 inhibition and highlight a novel function of PARP6 in maintaining centrosome integrity via direct ADP-ribosylation of Chk1 and modulation of its activity.Significance:These findings describe a new inhibitor of PARP6 and identify a novel function of PARP6 in regulating activation of Chk1 in breast cancer cells.

100 Deals associated with AZ0108

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	AstraZeneca PLC	01 Dec 2015

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