Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors

Caldarelli, Marina; Angiolini, Mauro; Disingrini, Teresa; Donati, Daniele; Guanci, Marco; Nuvoloni, Stefano; Posteri, Helena; Quartieri, Francesca; Silvagni, Marco; Colombo, Riccardo

doi:10.1016/j.bmcl.2011.05.122

Cited by 48 publications

(33 citation statements)

References 12 publications

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“…Quinazoline derivatives display a large panel of activities, including kinase inhibition. For instance, 6-arylquinazolines are potent inhibitors of CDC2-like kinases [6], and pyrazolo [4,3-h]quinazoline-3-carboxamides have been developed as antitumor agents targeting multi-cyclin-dependent kinases and act as potent MPS1 kinase inhibitor [7]. Closely related structures such as harmine [8] or pyrazolo [3,4-b]pyridine [9] show significant activities of DYRK1A and CDK5-GSK3 inhibitors, respectively.…”

Section: Introductionmentioning

confidence: 98%

Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors

et al. 2012

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A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N-ethoxycarbonyl-N'-(hetero) arylguanidines at 130 °C in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-f]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design.

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Section: Introductionmentioning

confidence: 98%

Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors

et al. 2012

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“…19 More recently, several selective small-molecule MPS1 inhibitors have been utilized to explore the cellular function of MPS1. 20,21 These include 3 (MPI-0479605), 22 4 (AZ3146), 23 5 (NMS-P715), 24,25 a series of selective diaminopyridine-based inhibitors exemplified by 6 (26) that demonstrates inhibition of growth of A549 human tumor xenografts, and a set of indazole-based inhibitors represented by 7 (27) (Figure 1). …”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)

et al. 2013

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The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

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“…The three cancer cell lines HCT-116, DLD-1 and U2OS were exposed to increasing concentrations of the known Mps1 inhibitors NMS-P715, 12 MPI-0479605, 15 reversine 17 and a derivative of NMS-P715, hereafter referred to as compound-5 (Cpd-5) 26 (Supplementary Figure 1). The treatment with different inhibitors reduced cell viability in all cases, nevertheless with different grades of sensitivity ( Supplementary Figures 2a-c).…”

Section: Resultsmentioning

confidence: 99%

“…Cpd-5 was synthesized as described in patent WO 2009156315 A1 from Nerviano Medical Sciences 26 ( Supplementary Figure 11). Structure 1 (25 g, 225 mmol) in toluene (500 ml) and EtOH (250 ml) was added to p-toluenesulfonic acid (5 g, 29 mmol).…”

Section: Synthesis Of Cpd-5mentioning

confidence: 99%

Predicting drug resistance before it occurs

Behjati

2015

Sci. Transl. Med.

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A Koch, A Maia, A Janssen 1 and RH MedemaMps1/TTK is a dual-specificity kinase, with an essential role in mitotic checkpoint signaling, which has emerged as a potential target in cancer therapy. Several Mps1/TTK small-molecule inhibitors have been described that exhibit promising activity in cell culture and xenograft models. Here, we investigated whether cancer cells can develop resistance to these drugs. To this end, we treated various cancer cell lines with sublethal concentrations of a potent Mps1/TTK inhibitor in order to isolate inhibitor-resistant monoclonal cell lines. We identified four point mutations in the catalytic domain of Mps1/TTK that gave rise to inhibitor resistance but retained wildtype catalytic activity. Interestingly, cross-resistance of the identified mutations to other Mps1/TTK inhibitors is limited. Our studies predict that Mps1/TTK inhibitor-resistant tumor cells can arise through the acquisition of mutations in the adenosine triphosphatebinding pocket of the kinase that prevent stable binding of the inhibitors. In addition, our results suggest that combinations of inhibitors could be used to prevent acquisition of drug resistance. Interestingly, cross-resistance seems nonspecific for inhibitor scaffolds, a notion that can be exploited in future drug design to evict possible resistance mutations during clinical treatment.

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Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors

Cited by 48 publications

References 12 publications

Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors

Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors

Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)

Predicting drug resistance before it occurs

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