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Published on: September 30, 2016
Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal
Hans-Peter Buchstaller1, Uwe Anlauf1, Dieter Dorsch1
1Merck KGaA, Global Research & Development, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Abstract:
Constitutive activation of the canonical Wnt signaling pathway, in most cases driven by inactivation of the tumor suppressor APC, is a hallmark of colorectal cancer. Tankyrases are druggable key regulators in these malignancies and are considered as attractive targets for therapeutic interventions, although no inhibitor has been progressed to clinical development yet. We continued our efforts to develop tankyrase inhibitors targeting the nicotinamide pocket with suitable drug-like properties for investigating effects of Wnt pathway inhibition on tumor growth. Herein, the identification of a screening hit series and its optimization through scaffold hopping and SAR exploration is described. The systematic assessment delivered M2912, a compound with an optimal balance between excellent TNKS potency, exquisite PARP selectivity, and a predicted human PK compatible with once daily oral dosing. Modulation of cellular Wnt pathway activity and significant tumor growth inhibition was demonstrated with this compound in colorectal xenograft models in vivo.
Insights
Researchers developed M2912, a potent and selective tankyrase inhibitor, to target the Wnt pathway in colorectal cancer. This compound effectively inhibited tumor growth in preclinical models, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Constitutive activation of the Wnt signaling pathway is a key driver of colorectal cancer, often due to APC tumor suppressor inactivation.
- Tankyrases are crucial regulators of this pathway and represent attractive therapeutic targets for colorectal cancer, though clinical inhibitors are lacking.
- Developing tankyrase inhibitors with drug-like properties is essential for exploring Wnt pathway inhibition in cancer treatment.
Purpose of the Study:
- To identify and optimize novel tankyrase inhibitors targeting the nicotinamide pocket for colorectal cancer therapy.
- To develop a compound with potent tankyrase inhibition, high PARP selectivity, and suitable pharmacokinetic properties for oral administration.
- To evaluate the efficacy of the optimized compound in modulating Wnt pathway activity and inhibiting tumor growth in vivo.
Main Methods:
- Screening for tankyrase inhibitors and subsequent optimization using scaffold hopping and structure-activity relationship (SAR) studies.
- Characterization of M2912 for its potency against TNKS (tankyrase) and selectivity over PARP enzymes.
- Assessment of M2912's pharmacokinetic profile and its ability to inhibit Wnt pathway activity and tumor growth in colorectal cancer xenograft models.
Main Results:
- Identification and optimization of a screening hit series led to the development of M2912.
- M2912 exhibits excellent TNKS potency, high PARP selectivity, and predicted human pharmacokinetics suitable for once-daily oral dosing.
- M2912 demonstrated modulation of cellular Wnt pathway activity and significant tumor growth inhibition in colorectal xenograft models.
Conclusions:
- M2912 is a promising drug candidate with a favorable profile for targeting tankyrases in colorectal cancer.
- The compound effectively inhibits the Wnt pathway and demonstrates significant anti-tumor activity in preclinical models.
- Further development of M2912 could lead to novel therapeutic strategies for colorectal cancer patients.
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