Discovery of a Class of Novel Tankyrase Inhibitors that Bind to Both the Nicotinamide Pocket and the Induced Pocket

Abstract

Potent and selective inhibitors of tankyrases have recently been characterized to bind to an induced pocket. Here we report the identification of a novel potent and selective tankyrase inhibitor that binds to both the nicotinamide pocket and the induced pocket. The crystal structure of human TNKS1 in complex with this "dual-binder" provides a molecular basis for their strong and specific interactions and suggests clues for the further development of tankyrase inhibitors.

Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics

“…18,19 Also dual binders interacting with both of the subsites have recently been developed. 20,21 The hit compounds identified in this study bind to the NI subsite similarly to several other previously characterized ARTD inhibitors, such as 1 (XAV939). We utilized the available structural data in structure-based virtual screening approach with an aim to identify new tankyrase inhibitor scaffolds.…”

Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling

“…Highly selective and potent inhibitors of TNKS (TNKSi) have been developed and characterized in different cancer models (8,(13)(14)(15)(16)(17), including colorectal cancer in which constitutive Wnt activity is a major driver of tumor maintenance (18,19). However, inhibition of TNKS is not sufficient to fully suppress Wnt signaling, resulting in only partial tumor growth inhibition (15).…”

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

“…21−23 Very recently, some quinazolin-4-ones carrying (CH 2 ) 2 CONHAr at position-2 have been reported as binding both to the nicotinamide-binding site and at an induced pocket. 24 A crystal structure of 1 bound into the nicotinamide-binding region of the catalytic domain of TNKS-2 was published in 2010, 25 Figure 1.…”