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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
The WEE 1 tyrosine kinase regulates entry into mitosis by arresting cells with DNA damage at the G2 phase. Since tumor cells lack normal DNA repair mechanisms, they rely heavily on this kinase to serve as a DNA damage checkpoint [93]. In conjunction with cytotoxic agents, inhibition of WEE 1 kinase (via the pyrazolopyrimidine derivative MK-1775) has been adopted for the study of adult solid tumors in Phase I/II trials (NCT01748825, NCT02095132, NCT01357161) [94]. In DAOY and UW228 medulloblastoma cell lines, MK-1775 at nanomolar concentrations inhibited colony formation. Furthermore, in nude mice injected with DAOY cells subcutaneously, oral treatment with MK-1775 led to tumor regression. When tested in conjunction with cisplatin, MK-1775 accelerated apoptosis and inhibited repair of cisplatin-induced DNA damage [92].
Structures of benzodiazepine recognition site ligands
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
The most recently introduced hypnotic, zaleplon, is a pyrazolopyrimidine analogue derived from this series which displays subtype selectivity (preferring BZ1 subtype receptors) and exhibits an elimination half-life of one hour (Figure 5.7) (Sanger et al, 1995; Beer et al, 1994, 1997; Hurst and Noble, 1999).
Sedative and Hypnotic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Arup Kumar Misra, Pramod Kumar Sharma
Zaleplon, pyrazolopyrimidine derivative binds on the allosteric site as zolpidem on α1 receptor benzodiazepine subunit of the GABAA receptors. Presystemic metabolism reduces its oral bioavailability to about 30%. In 1 h, the drug reaches its peak plasma level after rapid absorption (Rosen et al., 1999). It is metabolized to inactive metabolites partly by hepatic aldehyde oxidase and cytochrome P450 isoform CYP3A4. In hepatic impairment patients and in geriatric age group, adjustment of dose may be required. It has interaction with drugs whose metabolism involves cytochrome P450 and aldehyde oxidase pathway (Rosen et al., 1999). Enzymes inhibitors may markedly increase the peak plasma concentration of zaleplon as they inhibit CYP3A4 and aldehyde dehydrogenase. Oxidation and glucuronidation of zaleplon produced soluble metabolites which are excreted through urine and reducing the plasma half-life to about 1 h. The drug is available in 5, 10, and 20 mg doses. Chronic or transient insomnia patient treated with zaleplon may experience shorter periods of sleep onset latency (Atkin et al., 2018).
An updated patent review of small-molecule ROS1 kinase inhibitors (2015–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Meng Liu, Jintian Dai, Mudan Wei, Qingshan Pan, Wufu Zhu
A compound published by WO2017013160A1 containing a pyrazolopyrimidine structure, which demonstrated inhibitory activity against a variety of kinases. The molecular docking result of compound 34 with apoenzyme (ROS1 without endogenous ligand, PDB code: 4UXL) by Autodock 4.0 software was shown in the Figure 16. This compound has formed two key hydrogen bonds with Glu2027 and Met2029 residues respectively which insured the capability to overcome the mutation resistances. In the cell viability test, compound 34 showed varying degrees of inhibition on cells containing ROS1 gene and ROS1 mutant genes. The IC50 for HCC78 cells (expressing ROS1-SLC34A2 gene) was 0.92 μM, the IC50 for CD74-ROS1WT cells was 1.9 μM, and the IC50 for CD74-ROS1 G2032R (expressing ROS1 mutant gene) cells was 2 nM [73].
Have molecular hybrids delivered effective anti-cancer treatments and what should future drug discovery focus on?
Published in Expert Opinion on Drug Discovery, 2021
Mao et al. reported the synthesis of pyrazolopyrimidines, useful for treating cancer-related to the dysregulation of kinase pathways. The synthesized hybrids were screened in vitro using a panel of cMet addicted cancer cell line (H1993). Most of the synthesized compounds exhibited EC50 in sub-micromolar concentrations with the most active hybrid, 18, having EC50 in the range of 0.12–0.29 µM. The compounds, however failed to show any anti-proliferative effects on cMet-non-addicted cell line displaying their specific cMet inhibition tendency. Further, the promising compounds were evaluated for their enzymatic activities on purified cMet protein and were found to have IC50s in lower nM range [55].
Pharmaceutical agents for treatment of leishmaniasis: a patent landscape
Published in Expert Opinion on Therapeutic Patents, 2020
Yasmim Maria Barbosa Gomes de Carvalho, Saravanan Shanmugam, Mayrton Santos Batista, Mairim Russo Serafini, Adriano Antunes De Souza Araújo, Lucindo José Quintans Júnior
Pyrazolopyrimidines are a series of isomeric heterocyclic chemical compounds which forms the central core of a variety of more complex chemical compounds including some pharmaceuticals and pesticides [15]. The inventors Gilbert and Thomas [16] provide that the composition of pyrazolopyrimidines compounds including 3,3,3-trifluoro-a/- ((l,4-irans)-4-((4-methoxy-3-(2-methoxyphenyl)-l/-/-pyrazolo [3,4-d] pyrimidin-6-yl)amino) cyclohexyl) propane-l-sulfonamide can be used in the treatment of leishmaniasis, particularly visceral leishmaniasis treatment.