PI3Kδ inhibitors have been
developed for treatment of B-cell
malignancies and inflammatory and autoimmune diseases. However, their
therapeutic role in solid tumors like hepatocellular carcinoma (HCC)
is rarely reported. Thus, the development of potent and selective
PI3Kδ inhibitors with a new chemotype and therapy is highly
desirable. Through the scaffold-hopping strategy, indazole was first
described as the core structure of propeller-shaped PI3Kδ inhibitors.
A total of 26 indazole derivatives were designed and prepared to identify
a novel compound 9x with good isoform selectivity, PK
profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic
(PD) studies showed that 9x exhibits superior efficacy
in HCC cell lines and xenograft models, and the mechanistic study
showed that 9x robustly suppresses the downstream AKT
pathway to induce subsequent apoptotic cell death in HCC models. Therefore,
this work provides a new structural design of PI3Kδ inhibitors
for a novel and efficient therapeutic small molecule toward HCC.
:
Epilepsy is a chronic brain disorder caused by abnormal firing of neurons. Up to now, using antiepileptic drugs is the main method of epilepsy treatment. The development of antiepileptic drugs lasted for centuries. In general, most agents entering clinical practice act on the balance mechanisms of brain “excitability-inhibition”. More specifically, they target voltage-gated ion channels, GABAergic transmission and glutamatergic transmission. In recent years, some novel drugs representing new mechanisms of action have been discovered. Although there are about 30 available drugs in the market, it is still in urgent need of discovering more effective and safer drugs. The development of new antiepileptic drugs is into a new era: from serendipitous discovery to evolutionary mechanism-based design. This article presents an overview of drug treatment of epilepsy, including a series of traditional and novel drugs.
The
androgen receptor (AR) antagonists are efficient therapeutics
for the treatment of prostate cancer (PCa). All the approved AR antagonists
to date are targeted to the ligand-binding pocket (LBP) of AR and
have suffered from various drug resistances, whereas AR antagonist
targeting non-LBP site of AR is conceived as a promising strategy.
Through the scaffold hopping of AR LBP antagonists, the 2-chloro-4-(1H-pyrazol-1-yl)benzonitrile was designed as a new core structure
for AR antagonists. A total of 46 compounds were synthesized and biologically
evaluated to disclose compounds 2f, 2k,
and 4c, exhibiting potent AR antagonistic activities
(IC50 up to 69 nM), force against antiandrogen resistance,
and untraditional targeting site of probably AR binding function 3.
Therein, 4c exhibited effective tumor growth inhibition
in LNCaP xenograft study upon oral administration. This work provides
a novel chemical scaffold for AR antagonists and offers new perspective
for the development of PCa therapy.
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