NMS-P118 / Nerviano Medical Sciences - LARVOL DELTA

Cooperative molecular interaction networks govern PARP1 inhibitor selectivity and binding affinity. (PubMed, PLoS Comput Biol) - "To explore the molecular determinants of ligand selectivity, we focus on four clinically relevant PARP inhibitors-two PARP1-selective (saruparib and NMS-P118) and two non-selective (veliparib and olaparib) inhibitors-and perform atomistic potential-of-mean-force calculations of the PARP1 catalytic binding domain in the presence of these molecules. Progressively increasing the number of mutations markedly reduces binding stability, with distinct residue combinations exerting two primary effects: destabilization of the final bound state and the emergence of energetic barriers along the ligand association pathway. Together, our results provide a coherent mechanistic framework for understanding PARP1 selectivity and informs the rational design of next-generation inhibitors with improved efficacy and safety."

Journal • Hematological Disorders • Oncology • BRCA • PARP2

Clonorchis sinensis aggravated liver fibrosis by activating PARP-1 signaling to induce parthanatos via DNA damage. (PubMed, Vet Parasitol) - "Our data indicated that C. sinensis and its ESPs could activate PARP-1 signaling to induce cellular parthanatos. NMS-P118 treatment alleviated liver fibrosis and promoted survival of the mice by inhibiting PARP-1, which suggested that PARP-1 could be used as a potential therapeutic target against clonorchiasis."

Journal • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hepatology • Immunology • Infectious Disease • Liver Cirrhosis • Oncology • Solid Tumor

[VIRTUAL] Structure-based and property-based drug design of AZD5305, a highly selective PARP1 inhibitor and trapper (AACR 2021) - "Since the approval of olaparib in 2014 for BRCA mutated (BRCAm) ovarian cancer, many PARP inhibitors have been developed and have seen widespread success...The publication of NMS-P118 in 2015 by Nerviano Medical Sciences showed that a highly selective PARP1 inhibitor could be found...The secondary pharmacology of AZD5305 is remarkably clean, with hERG activity >40 µM. AZD5305 has a very favorable pre-clinical PK profile, low predicted human dose, and has shown efficacy in an MDA-MB-436 mouse xenograft model."

Oncology • Ovarian Cancer • Solid Tumor • BRCA • BRCA2 • PARP2