2. Academic Validation
  3. The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models

The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models

  • Cancer Res. 2016 Oct 15;76(20):6084-6094. doi: 10.1158/0008-5472.CAN-15-3240.
Lenka Oplustil O'Connor 1,  Stuart L Rulten 2,  Aaron N Cranston 3,  Rajesh Odedra 1,  Henry Brown 1,  Janneke E Jaspers 4,  Louise Jones 3,  Charlotte Knights 3,  Bastiaan Evers 5,  Attilla Ting 1,  Robert H Bradbury 1,  Marina Pajic 6,  Sven Rottenberg 6,  Jos Jonkers 5,  David Rudge 1,  Niall M B Martin 3,  Keith W Caldecott 2,  Alan Lau 1,  Mark J O'Connor 7
Affiliations

Affiliations

  • 1 AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
  • 2 Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, United Kingdom.
  • 3 KuDOS Pharmaceuticals Ltd, Cambridge, United Kingdom.
  • 4 Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 5 Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 6 Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 7 AstraZeneca, Alderley Park, Macclesfield, United Kingdom. mark.j.oconnor@astrazeneca.com.
PMID: 27550455 DOI: 10.1158/0008-5472.CAN-15-3240
Abstract

The PARP Inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP Inhibitor approved for Cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability. Cancer Res; 76(20); 6084-94. ©2016 AACR.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13536
    99.88%, PARP抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z