1. Academic Validation
  2. Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization

  • Bioorg Med Chem. 2020 Dec 15;28(24):115819. doi: 10.1016/j.bmc.2020.115819.
Navnath P Karche 1 Mandar Bhonde 2 Neelima Sinha 2 Gourhari Jana 2 Gagan Kukreja 2 Sanjay P Kurhade 2 Arun R Jagdale 2 Ajay R Tilekar 2 Anil K Hajare 2 Ganesh R Jadhav 2 Nishant R Gupta 2 Rohan Limaye 2 Nilesh Khedkar 2 Baban R Thube 2 Javed S Shaikh 2 Nageswara Rao Irlapati 2 Samiron Phukan 2 Gopal Gole 2 Apparao Bommakanti 2 Harshal Khanwalkar 2 Yogesh Pawar 2 Ramesh Kale 2 Rakesh Kumar 2 Rajesh Gupta 2 V R Praveen Kumar 2 Saif Wahid 2 Albi Francis 2 Tariq Bhat 2 Nivrutti Kamble 2 Vinod Patil 2 Prashant B Nigade 2 Dipak Modi 2 Shashikant Pawar 2 Sneha Naidu 2 Harish Volam 2 Vamsi Pagdala 2 Sadanand Mallurwar 2 Hemant Goyal 2 Pushpak Bora 2 Prajakta Ahirrao 2 Minakshi Singh 2 Prabhakaran Kamalakannan 2 Kumar Ram Naik 2 Pradipta Kumar 2 Rajendra G Powar 2 Rajesh B Shankar 2 Peter R Bernstein 2 Jayasagar Gundu 2 Kumar Nemmani 2 Lakshmi Narasimham 2 Kochumalayil Shaji George 2 Sharad Sharma 2 Dhananjay Bakhle 2 Rajender Kumar Kamboj 2 Venkata P Palle 2
Affiliations

Affiliations

  • 1 Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India. Electronic address: navnathkarche@lupin.com.
  • 2 Novel Drug Discovery & Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi, Pune 412115, India.
Abstract

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 Inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast Cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast Cancer, pancreatic Cancer and Ewing's sarcoma models.

Keywords

Binding modes; PARP inhibition; Safety; Selectivity; Tumor regression.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-142657
    99.80%, PARP 抑制剂