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  • br Conclusion In summary screening a small compound library

    2024-02-04


    Conclusion In summary, screening a small compound library based on the 3-aminopyridin-2-one motif in a target-blind manner against a 26-kinase panel, representative of the kinome, identified hits that possess good activity and excellent ligand efficiency against MPS1, Aurora A and Aurora B. The binding mode of fragment 2 and compounds 22 and 23 with MPS1 was elucidated using X-ray crystallography providing structural information that could prove valuable in improving potency and obtaining a desirable selectivity profile. This scaffold may prove an attractive starting point for the development of potent inhibitors of MPS1 by providing vectors suitable for probing the P-loop, as in NMS-P715, or positioning of a hydrophobic group in a manner that further orders the activation loop.41, 44
    Experimental section Chemistry: All anhydrous solvents and reagents were obtained from commercial suppliers (Sigma Aldrich, Acros, Fluorochem, Alfa Aesar) and used without further purification. Reactions were performed in oven-dried, round-bottom flasks fitted with rubber septa under an TPPU australia of argon unless otherwise stated. Analytical thin layer chromatography (TLC) was performed on pre-coated aluminium sheets of silica (60 F254, Merck) and visualised by short-wave UV light. Reactions using microwave irradiation were performed in a Biotage® Initiator Sixty. Flash column chromatography was performed on a FlashMaster personal unit using isolute Flash silica columns or a Biotage SP1 purification system using Biotage Flash silica cartridges. Ion exchange chromatography was performed using acidic Isolute Flash SCX-II cartridges. Silicon carbonate columns used were Isolute Si-Carbonate from Biotage. 1H NMR spectra were recorded at 500 MHz on a Bruker Avance-500 using an internal deuterium lock. Chemical shifts were measured in parts per million (ppm) relative to tetramethylsilane (δ = 0) using the following internal references for residual protons in the solvent: CDCl3 (δ 7.26), CD3OD (δ 3.32) and (CD3)2SO (δ 2.50). Data is presented as follows: chemical shift, integration, multiplicity, coupling constant (J) in Hz. 13C NMR spectra were recorded at 126 MHz on a Bruker Avance-500 using an internal deuterium lock. Chemical shifts were measured in parts per million (ppm) relative to tetramethylsilane (δ = 0) using the following internal references: CDCl3 (δ 77.0), CD3OD (δ 49.0) and (CD3)2SO (δ 39.5). Data is presented as follows: chemical shift, integration, multiplicity, coupling constant (J) in Hz. HRMS analysis was performed on an Agilent 1200 series HPLC and diode array detector coupled to a 6520 Quadrupole-Time of flight mass spectrometer with dual multimode APCI/ESI source. Analytical separation (Method A) was carried out at 30 °C on a Merck Purospher STAR column (RP-18e, 30 x 4 mm) using a flow rate of 1.5 mL/min in a 4 min gradient elution with detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B) both containing formic acid at 0.1%. Gradient elution was as follows: 1:9 (A/B) to 9:1 (A/B) over 2.5 min, 9:1 (A/B) for 1 min, and then reversion back to 1:9 (A/B) over 0.3 min, finally 1:9 (A/B) for 0.2 min. The following references masses were used for HRMS analysis: caffeine [M + H]+ 195.087652; hexakis(1H,1H,3H-tetrafluoropentoxy)phosphazene [M + H]+ 922.009798, and hexakis(2,2-difluoroethoxy) phosphazene [M + H]+ 622.02896 or reserpine [M + H]+ 609.280657.
    Introduction Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, accounting for more than 600,000 cases globally each year [1]; more than 50,000 new cases occur annually in the United States alone [2]. For several decades, the decline in tobacco-associated HNSCC has been met with an increase in human papillomavirus (HPV)-associated HNSCC, which is molecularly and epidemiologically distinct from HPV-negative HNSCC [3]. Nearly all cervical epithelial squamous carcinoma (CESC) is HPV-driven, and an estimated 72% of oropharyngeal squamous cancers in the United States have been associated with HPV infection [4]. It has been estimated that by 2020, HPV-positive HNSCC cases will outnumber HPV-driven CESC cases in the United States [3]. While this statistic highlights the successes of preventative care due to increased annual CESC screenings, there are still more than 4000 deaths annually from CESC in the United States, and there are no biomarker-selective targeted therapies for advanced CESC or HNSCC. Although patients with HPV-positive HNSCC have significantly better overall survival [5], about 25% of HPV-positive patients experience recurrence that is refractory to standard therapy [6]. These statistics demonstrate the need for biomarker-driven therapies for these cancers.