Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/β-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone 5 as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated.
From PARP1 to TNKS2 Inhibition: A Structure-Based Approach / Tomassi, S., Pfahler, J., Mautone, N., Rovere, A., Esposito, C., Passeri, D., Pellicciari, R., Novellino, E., Pannek, M., Steegborn, C., Paiardini, A., Mai, A., Rotili, D.. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 11:5(2020), pp. 862-868. [10.1021/acsmedchemlett.9b00654]
From PARP1 to TNKS2 Inhibition: A Structure-Based Approach
Tomassi SPrimo
Conceptualization
;Novellino E;
2020
Abstract
Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/β-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone 5 as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
