2. Academic Validation
  3. 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

  • ACS Med Chem Lett. 2015 Jan 13;6(3):254-9. doi: 10.1021/ml5003663.
Jeffrey W Johannes 1,  Lynsie Almeida 1,  Bernard Barlaam 2,  P Ann Boriack-Sjodin 1,  Robert Casella 1,  Rosemary A Croft 2,  Allan P Dishington 2,  Lakshmaiah Gingipalli 1,  Chungang Gu 1,  Janet L Hawkins 2,  Jane L Holmes 2,  Tina Howard 2,  Jian Huang 1,  Stephanos Ioannidis 1,  Steven Kazmirski 1,  Michelle L Lamb 1,  Thomas M McGuire 2,  Jane E Moore 2,  Derek Ogg 2,  Anil Patel 2,  Kurt G Pike 2,  Timothy Pontz 1,  Graeme R Robb 2,  Nancy Su 1,  Haiyun Wang 1,  Xiaoyun Wu 1,  Hai-Jun Zhang 1,  Yue Zhang 1,  Xiaolan Zheng 1,  Tao Wang 1
Affiliations

Affiliations

  • 1 AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 2 AstraZeneca R&D Alderley Park , Macclesfield, Cheshire SK10 4TG, United Kingdom.
PMID: 25815142 DOI: 10.1021/ml5003663
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.

Keywords

Caco2; PARP; Wnt; oncogenesis; pharmacokinetics; tankyrase.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12975
    99.65%, TNKS1/S2 Inhibitor