Identification of 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazoline Derivatives as a New Class of Orally and Selective Polo-Like Kinase 1 Inhibitors

Abstract

Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.

NMS-P937, an Orally Available, Specific Small-Molecule Polo-like Kinase 1 Inhibitor with Antitumor Activity in Solid and Hematologic Malignancies

“…Inhibition of kinase activity by NMS-P937 was assessed with an anion exchanger (Dowex 1 Â 8 resin 200-400 mesh)-based assay as previously described (21).…”

“…In our effort to develop selective small-molecule PLK1 inhibitors, we previously described a novel series of ATPcompetitive 4,5-dihydro-1H-pyrazolo [4,3-h]quinazoline derivatives (20,21). Here, we report the in vitro activity and in vivo pharmacokinetic, pharmacodynamic, and efficacy profiles of NMS-P937.…”

Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands

“…[47][48][49][50][51][52] It is interesting to note that some of the 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide analogs showed potent activities in inhibiting heat shock proteins, 50 and various kinases, 51,52 and thus possessing potent anti-cancer activity. Therefore, the tetrahydroindazole scaffold may possess some favorable abilities toward protein binding.…”

1,3‐Dipolar Cycloaddition of Nitrile Imines with Cyclic α‐β‐Unsaturated Ketones: A Regiochemical Route to Ring‐Fused Pyrazoles

“…In particular, the use of 2-cyclohexenone as a dipolarophile would lead directly to 7-oxotetrahydroindazoles, which are scaffolds for the synthesis of 1,3-Dipolar Cycloaddition of Nitrile Imines more complex 4,5-dihydro-1H-pyrazolo[4,3-h]quinazolines that are very promising as kinase inhibitors. [10] Such a protocol is synthetically equivalent to building a pyrazole onto conjugated five-, six-or seven-membered ring alkynones, which are usually inaccessible owing to their highly strained bond angles. [11] Few papers on 1,3-DC of cyclic enones have been reported in the literature.…”