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Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and WNT Pathway Inhibitors Suitable for in Vivo Pharmacology

Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and WNT Pathway Inhibitors Suitable for in Vivo Pharmacology

Jeffrey W Johannes, Lynsie Almeida, Bernard Barlaam, P Ann Boriack-Sjodin, Robert Casella, Rosemary A Croft, Allan P Dishington, Lakshmaiah Gingipalli, Chungang Gu, Janet L Hawkins, Jane L Holmes, Tina Howard, etc.

ACS Med Chem Lett. 2015 Jan 13;6(3):254-9.

PMID: 25815142

Abstract:

The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germline mutations of several Wnt pathway components, such as Axin, APC, and ß-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100-fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1645286754	AZ6102		1645286-75-4	Price

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