Structure-Based Design of 2-Aminopyridine Oxazolidinones as Potent and Selective Tankyrase Inhibitors

Abstract

Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 mouse tumor PD model.

Tankyrases: Structure, Function and Therapeutic Implications in Cancer

“…Earlier compounds in the series suffered from moderate cellular potencies and poor oral exposure but further optimization led to improvements, such as with compound 40 (CMP40), which had significantly improved cellular potencies and when dosed orally in mice, had unbound exposure levels over their cellular IC 50 values. This compound series was further optimized by combining features from a dual binder acquired from HTS [ 167 ]. The optimized compound (CMP4) added a hydrogen bond to a glycine (Gly1196 in TNKS1).…”

Small-Molecule Inhibitors of Wnt Signaling Pathway: Towards Novel Anticancer Therapeutics

“…In a subsequent animal study, compounds 88 and 89 were administered orally to mice bearing DLD-1 tumor. The in vivo efficacy was confirmed by measuring the Wnt-pathway biomarkers [37].…”

Metal‐Catalyzed Cross‐Coupling Reactions of Aminopyridines

“…Recently, the synthesis of structure 134 , based on a 2‐aminopyridine/oxazolidinone scaffold and displaying tankyrase inhibitory activity, with the aid of a Stille reaction was reported by Huang et al (Scheme ) 99. The Stille coupling between 2‐amino‐3‐bromopyridine derivative 132 and 2‐(tributylstannyl)pyrimidine ( 133 ) was performed in the presence of Pd(PPh 3 ) 4 /CuI and LiCl under microwave irradiation conditions, in 47 % yield.…”

“… Stille coupling between 2‐amino‐3‐bromopyridine derivative 132 and 2‐(tributylstannyl)pyrimidine ( 133 ) 99…”