Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors

Abstract

Fibroblast growth factor receptors (FGFRs) are important targets for cancer therapy. Herein, we describe the design, synthesis, and biological evaluation of a novel series of 1H-pyrazolo [3,4-b]pyridine derivatives as potent and selective FGFR kinase inhibitors. On the basis of its excellent in vitro potency and favorable pharmacokinetic properties, compound 7n was selected for in vivo evaluation and showed significant antitumor activity in a FGFR1-driven H1581 xenograft model. These results indicated that 7n would be a promising candidate for further drug development. Cancer, FGFR, inhibitor, pyrazolo[3,pyridine F ibroblast growth factors (FGFs) and their receptors regulate a wide range of biological functions, including embryogenesis, tissue repair, wound healing, and angiogenesis. 1−3 The fibroblast growth factor receptor (FGFR) family comprises four highly conserved transmembrane tyrosine kinase receptors (FGFR1−4), which are differentially activated by binding to a subset of 18 FGF ligands. 3,4 Upon FGF binding, FGFR undergoes dimerization and autophosphorylation, resulting in activation of downstream signaling pathways, such as the MAPK and PLCγ pathways. 4,5 These FGFR cascades play crucial roles in key cell behaviors, such as proliferation, survival, differentiation, and migration, which makes FGFR signaling susceptible to subversion by cancer cells. 6 Dysregulation of FGFR signaling has been documented in clinical samples of bladder, lung, breast cancers, etc., 7 and aberrant FGFR activation is closely correlated with metastatic progression and poor prognosis. 8,9 Knockdown studies and pharmaceutical inhibition of FGFRs in preclinical models have further demonstrated that FGFRs are attractive targets for cancer therapy. 4,7,10 In recent years, many small molecules have been in clinical development, such as nintedanib, dovitinib, and cediranib, which are reported to target FGFR. 11 However, because of the high degree of homology of FGFRs with VEGFRs, most of these compounds have multitarget specificity, which leads to undesired side effects in their anticancer therapies. 12,13 Thus, discovery of highly selective FGFR inhibitors is an unmet medical need. Currently, several selective FGFR inhibitors have progressed robustly into clinical trials, such as NVP-BGJ398, 14 AZD4547, 15 and CH5183284 16 (Figure 1). PD173074 (Figure 1), the first reported selective FGFR inhibitor, inhibits FGFR1 with an IC 50 value of 21.5 nM at the molecular level, while inhibiting PDGFR, c-Src and EGFR, as well as several serine/threonine kinases with 1000-fold or greater IC 50 values. 17 Nevertheless, PD173074 exhibits submicromolar inhibitory activity at the cellular level against VEGFR2 (IC 50 = 100−200 nM). 17 The crystal structure of PD173074 in complex with the FGFR1 kinase domain elucidates that its high affinity and selectivity for FGFR1 stem from the presence of 3,5-dimethoxy phenyl ring that adopts an almost perpendicular orientation to the plane of the KEYWORDS:

Recent Advances in the Development of Indazole‐based Anticancer Agents

“…ChemMedChem 2018ChemMedChem , 13,1490ChemMedChem -1507 www.chemmedchem.org particular, Zhao et al described ac lass of 1H-pyrazolo [3,4b]pyridine derivatives as potent and selective FGFRs inhibitors using the same strategy. [39] Notably,s ubstitution from the 1Hindazole to 1H-pyrazolo [3,4-b]pyridine resulted in as ignificant increasei ne nzymatic potency, suggestingt hat, in some cases, indazole can be used as building block for preparation of more potent compounds. In this study,c ompound 15 was documentedt oh ave many outstanding in vitro and in vivo biological properties.…”

Polyethylene glycol (PEG‐400) Mediated One‐pot Green Synthesis of 4,7‐Dihydro‐2H‐pyrazolo[3,4‐b]pyridines Under Catalyst‐free Conditions

“…Among the N ‐heterocycles, the fused pyrazolo‐pyridine derivatives have received considerable attention because of their broad‐spectrum of biological profiles and thus constitute a versatile synthetic building block in drug discovery. Many of these possess various pharmacological activities including FGFR kinase inhibition, [16] antiproliferative, [17] antimicrobial and anticancer, [18] hPPAR α agonist [19] and human A1 adenosine antagonist activities [20] . Therefore, the preparation of pyrazolo[3,4‐ b ]pyridine scaffolds is highly desirable for their immense biological applications.…”

Design, One Pot Synthesis and Molecular Docking Studies of Substituted-1H-Pyrido[2,1-b] Quinazolines as Apoptosis-Inducing Anticancer Agents

“…Recent years fused heterocyclic compounds have gained a renewed attention because of their significant biological activities, some of them Pyrido [2,1-b]quinazoline carboxamide motifs as antiplatelet activity, pyrido [2',3':3,4] pyrazolo [1, 5-a] quinazoline (VI) as anticancer and antimicrobial activity (Kumar et al, 2018b) have been reported in the literature. Pyrazolo [3, 4-b]pyridine derivative (VII) have known to possess antitumor, antiviral, antimicrobial and anti-inflammatory activities (Nagender et al, 2014;Zhao et al, 2016) (Figure 1). Previously, many reports have known for versatile one pot, three component reaction of aminopyrimidine, ketone and aldehydes leading to synthesis of diverse fused heterocyclic rings such as Pyrido [2,1-b]quinazoline by using different catalyst (Yang et al, 2013;Sagir et al, 2016).…”