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

Johannes, Jeffrey W.; Almeida, Lynsie; Barlaam, Bernard; Boriack-Sjodin, P.A.; Casella, R.; Croft, Rosemary A.; Dishington, Allan; Gingipalli, Lakshmaiah; Gu, Chungang; Hawkins, Janet; Holmes, J. L.; Howard, Tina D.; Huang, Jian; Ioannidis, Stephanos; Kazmirski, Steven L.; Lamb, Michelle L.; McGuire, Thomas M.; Moore, Jane E.; Ogg, D.; Patel, Anil S.; Pike, Kurt G.; Pontz, Timothy; Robb, Graeme R.; Su, Nancy; Wang, Haiyun; Wu, Xia; Zhang, Haijun; Zhang, Yue; Zheng, Xiaolan; Wang, Tao

doi:10.1021/ml5003663

Cited by 58 publications

(65 citation statements)

References 22 publications

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“…Good progress has been made with the tankyrases, and several cell-active, potent, and selective tankyrase inhibitors are now available. 16–18 At the same time, attempts have been made to standardize in vitro assay technology and to characterize PARP inhibitors in terms of selectivity. 19,20 However, most PARP inhibitors have yet been profiled only against a handful of family members, rarely including any representative of the mono-ADP-ribosyltransferase subfamily.…”

Section: Introductionmentioning

confidence: 99%

Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

et al. 2016

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Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.

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Section: Introductionmentioning

confidence: 99%

Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

et al. 2016

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“…A recent high throughput proteomics screen identified the pyrimidinone nicotinamide mimetic, AZ1366, as a potent and selective inhibitor of TNSK1/2 with good bioavailability in mouse and rat and activity within the canonical Wnt pathway in DLD-1 cells (AZ1366 = Compound 9) (28). To confirm that AZ1366 effectively inhibits tankyrase and has activity within the canonical Wnt pathway in lung cancer cells, we treated HCC4006 cells with various concentrations of AZ1366.…”

Section: Resultsmentioning

confidence: 99%

“…Recent work highlighting the role of the tankyrases in the control of canonical WNT signaling has fueled interest in the development of inhibitors to target this enzyme (24). Numerous studies have shown that inhibition of tankyrase can induce cell killing in Wnt-dependent models of colorectal cancer, and the growing body of knowledge on the importance of the Wnt pathway and β-catenin in multiple cancers has stimulated several directed discovery efforts for tankyrase inhibitors (25–28). …”

Section: Introductionmentioning

confidence: 99%

AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non–Small Cell Lung Cancer Cells Following EGFR Inhibition

Scarborough

Helfrich

Casás‐Selves

et al. 2017

Clinical Cancer Research

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Purpose The emergence of EGFR-inhibitors such as gefitinib, erlotinib and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR-inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors. Experimental Design We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its anti-tumor activity, impingement on canonical Wnt signaling and effects on gene expression. We performed pharmacokinetic (PK) and pharmacodynamic (PD) profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model. Results In combination with EGFR-inhibitors, AZ1366 synergistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR-inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. PK and PD profiling of AZ1366-treated orthotopic tumors demonstrated clinically-relevant serum drug levels and intratumoral target inhibition. Finally, co-administration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model. Conclusions Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a co-treatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC.

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“…10 Treatment of DLD-1(APC mutant) cells with 2 inhibits β-catenin phosphorylation and decreases Wnt-mediated gene transcription as shown in a Luciferase reporter assay in APC mutant DLD-1 cells (IC 50 = 0.06 μM). 11 In an acute dose pharmacokinetic/pharmacodynamic (PK/PD) study, treatment of DLD-1/AKT1 overexpressing murine xenografts with 2 (10 mg/kg, PO) resulted in the 20% inhibition of Wnt-mediated luciferase gene transcription at 8 h, and coincided with an unbound drug concentration at the level of the Wnt reporter IC 50 . When tested in disease model studies using a murine DLD-1(APC mut ) xenograft, compound 2 showed limited tumor growth inhibition.…”

mentioning

confidence: 99%

Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo

Dowling

Alimzhanov

Bao

et al. 2016

ACS Med. Chem. Lett.

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ABSTRACT:The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development and adult tissue regeneration. Impaired Wnt pathway regulation, arising from mutations in Wnt signaling components, such as Axin, APC, and β-catenin, results in uncontrolled cell growth and triggers oncogenesis. To explore the reported link between CK2 kinase activity and Wnt pathway signaling, we sought to identify a potent, selective inhibitor of CK2 suitable for proof of concept studies in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (2), we identified compound 7h, a potent CK2 inhibitor with picomolar affinity that is highly selectivity against other kinase family enzymes and inhibits Wnt pathway signaling (IC 50 = 50 nM) in DLD-1 cells. In addition, compound 7h has physicochemical properties that are suitable for formulation as an intravenous solution, has demonstrated good pharmacokinetics in preclinical species, and exhibits a high level of activity as a monotherapy in HCT-116 and SW-620 xenografts. KEYWORDS: CK2 kinase, pyrazolo[1,5-a]pyrimidine, Wnt, β-catenin T he serine/threonine protein kinase CK2 is a constitutively active heterotetrameric complex composed of two catalytic (α or α′) and two regulatory (β) subunits, 1 which has emerged as an attractive drug discovery target in oncology. 2 Researchers from Cylene have recently advanced CX-4945, a selective, orally available inhibitor of CK2 into the clinic for treatment of patients with solid tumors and hematological malignancies. 3 Among its diverse functions, CK2 interacts with and regulates multiple components of the Wnt pathway, an evolutionarily conserved signaling network that regulates embryonic development and the regeneration of intestinal epithelial cells. 4 Certain cancers, including colorectal carcinoma (CRC), arise due to gene mutations among constituents of the Wnt pathway, including the CK2 substrates dishevelled (Dvl), APC, and β-catenin. 5 Inhibition of CK2, either by RNA knockdown or with small molecules, decreases β-catenin−Tcfmediated transcription of Wnt target genes such as survivin and leads to cell death and apoptosis in a range of CRC lines. 6,7 In addition, elevated levels of CK2 activity have been reported in CRC tissue samples and expression levels correlate with poor prognosis in CRC patients. 8,9 Taken together, these data illustrate the potential utility of CK2 inhibitors in CRC and other cancers characterized by aberrant Wnt pathway activity.We sought to identify a potent, selective inhibitor of CK2 kinase for hypothesis testing in vivo using preclinical models of CRC. An early probe from our previously described series of ATP-competitive pyrazolo[1,5-a]pyrimidine-derived inhibitors of CK2 (1, 2; Figure 1) was used to assess the link between CK2 inhibition and Wnt signaling. 10 Treatment of DLD-1(APC mutant) cells with 2 inhibits β-catenin phosphorylation and decreases Wnt-mediated gene transcription as shown in a Luciferase reporter assay in APC

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

Cited by 58 publications

References 22 publications

Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non–Small Cell Lung Cancer Cells Following EGFR Inhibition

Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo

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