Synthetic Heterocyclic Derivatives as Kinase Inhibitors Tested for the Treatment of Neuroblastoma

Abstract

In the last few years, small molecules endowed with different heterocyclic scaffolds have been developed as kinase inhibitors. Some of them are being tested at preclinical or clinical levels for the potential treatment of neuroblastoma (NB). This disease is the most common extracranial solid tumor in childhood and is responsible for 10% to 15% of pediatric cancer deaths. Despite the availability of some treatments, including the use of very toxic cytotoxic chemotherapeutic agents, high-risk (HR)-NB patients still have a poor prognosis and a survival rate below 50%. For these reasons, new pharmacological options are urgently needed. This review focuses on synthetic heterocyclic compounds published in the last five years, which showed at least some activity on this severe disease and act as kinase inhibitors. The specific mechanism of action, selectivity, and biological activity of these drug candidates are described, when established. Moreover, the most remarkable clinical trials are reported. Importantly, kinase inhibitors approved for other diseases have shown to be active and endowed with lower toxicity compared to conventional cytotoxic agents. The data collected in this article can be particularly useful for the researchers working in this area.

Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting

“…57 contained a 1,3-dimethyl-benzimidazolone moiety gave rise to a similar DSF shift compared to the aromatic counterparts and a similar binding mode compared to the aforementioned ATP mimetic groups (Figure 4G). The transition from traditional aromatic heterocyclic systems that have been almost exclusively used in the development of kinase inhibitors 46,47 to saturated ring systems could not only yield more favorable selectivity profiles, but may also improve physicochemical and pharmacokinetic properties of inhibitors. 48,49 Motivated by this finding, we expanded the spectrum of saturated ring systems (28,33,34,41,46,47,57).…”

Applications of palladium-catalyzed C–N cross-coupling reactions in pharmaceutical compounds

“…Screening various reaction conditions achieved excellent optimization that led good conversion yield of the nal product. [132][133][134] In continuation, paying attention to the goals of green chemistry encouraged researchers to investigate abemaciclib synthesis by Pd-free catalytic systems and in more sustainable reaction conditions. Successful outcomes of magnetic cobalt-catalyzed C-N coupling in the abemaciclib preparation process have opened new horizons in the development of green chemistry in medicinal chemistry.…”

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

“…Known as JNJ-42756493, this compound is already approved by the FDA for the treatment of advanced or metastatic urothelial carcinoma, and is now under clinical trials that also include childhood CNS tumors [ 736 ]. It inhibits FGFR1/2/3/4 with increasing IC 50 values of 1.2, 2.5, 3.0 and 5.7 nM, respectively [ 737 ]. This compound inhibited proliferation on five different NB cell lines (SK-N-AS, SK-N-BE(2)-C, SK-N-DZ, SK-N-FI and SK-N-SH) as monotherapy, but showed variable synergistic, additive and antagonistic effects when combined with commonly used cytotoxic agents such as cisplatin, vincristine and doxorubicin [ 738 ].…”