Discovery of novel pyrazole derivatives as potential anticancer agents in MCL.

Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton's tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19'c, 21c and 21'c showed potent effect in MCL cells with IC50 values lower than 1 µM, and a more than 3-28-fold increase in antiproliferative activity compared with IBN.

Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with effective anticancer activity in MCL.

Bruton's tyrosine kinase (BTK) is a key regulator of B-cell receptor (BCR) signaling pathway and takes effect in the regulation of B-cell activation, survival, proliferation and differentiation. It has been proved that BTK is commonly overexpressed in mantle cell lymphoma (MCL), which makes it a focus of targeted therapy for MCL. Our studies yielded a novel series of pyrazolopyrimidine derivatives capable of potent inhibition of BTK. Notably, 12a showed higher selectivity against BTK and exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 12a induced strong cell apoptosis in Jeko-1 and Z138 cells.

Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases: Preclinical and clinical developments of small molecule inhibitors.

B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton's tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib. Constantly emerging agents exhibiting superior efficacy and safety in preclinical and clinical studies provide promising therapeutics for the treatment of B cell malignancies.

Synthesis and biological evaluation of 3-(4-fluorophenyl)-1H-pyrazole derivatives as androgen receptor antagonists.

A novel series of 3-(4-fluorophenyl)-1H-pyrazole derivatives were synthesized and evaluated for their antiproliferative activity against two prostate cancer cell lines (LNCaP and PC-3) and androgen receptor target gene prostate-specific antigen (PSA) inhibitory activity in LNCaP cells. Several compounds showed potent antiproliferative activity against LNCaP cells and showed a promising PSA downregulation rate. Among these, compound 10e selectively inhibited LNCaP cell growth with an IC50 value of 18 µmol/l and showed a PSA downregulation rate of 46%, which was better than the lead compound T3.

Recent Developments in Androgen Receptor Antagonists.

The androgen receptor (AR), a ligand-dependent transcription factor that regulates the expression of a series of downstream target genes after the binding of androgens, has been a target for the discovery of drugs used to treat prostate cancer. Prostate cancer always progresses to castration-resistant prostate cancer after a period of androgen deprivation therapy. Thus, developing potent androgen receptor antagonists for the therapy of castration-resistant prostate cancer possesses great significance. This review summarizes the preclinical development of androgen receptor antagonists, conventional androgen receptor antagonists that competitively bind to the ligand binding domain of the androgen receptor and coactivator antagonists of the androgen receptor, including both activation function-2 antagonists and binding function-3 antagonists. We hope that this review can help other researchers find new scaffolds and sites for the treatment of prostate cancer.

Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase.

Raltegravir (RAL) is a first clinically approved integrase (IN) inhibitor for the treatment of HIV but rapid mutation of the virus has led to chemo-resistant strains. Therefore, there is a medical need to develop new IN inhibitors to overcome drug resistance. At present, several IN inhibitors are in different phases of clinical trials and few have been discontinued due to toxicity and lack of efficacy. The development of potent second-generation IN inhibitors with improved safety profiles is key for selecting new clinical candidates. In this article, we report the design and synthesis of potent 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide analogues as second-generation IN inhibitors. These compounds satisfy two structural requirements known for potent inhibition of HIV-1 IN catalysis: a metal chelating moiety and a hydrophobic functionality necessary for selectivity against the strand transfer reaction. Most of the new compounds described herein are potent and selective for the strand transfer reaction and show antiviral activity in cell-based assays. Furthermore, this class of compounds are drug-like and suitable for further optimization and preclinical studies.

Design, synthesis and biological evaluation of AKT inhibitors bearing a piperidin-4-yl appendant.

A series of AKT inhibitors possessing a piperidin-4-yl side chain was designed and synthesized. Some of them showed high AKT1 inhibitory activity and potent anti-proliferative effect on PC-3 prostate cancer cells in the preliminary screening. Further studies revealed the most potent compound, 10h, as a pan-AKT inhibitor. Compound 10h was able to inhibit the cellular phosphorylation of AKT effectively and induce apoptosis of PC-3 cells. It also showed high metabolic stability in human liver microsomes. Preclinical characterization of 10h, a promising lead AKT inhibitor, as a potential anti-prostate cancer therapeutic needs to be further investigated.

Discovery of novel 5-methyl-1H-pyrazole derivatives as potential antiprostate cancer agents: Design, synthesis, molecular modeling, and biological evaluation.

Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration-resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability compared with 10e in human liver microsomes.

Structural optimization elaborates novel potent Akt inhibitors with promising anticancer activity.

Targeting of Akt has been validated as a well rationalized approach to cancer treatment, and represents a promising therapeutic strategy for aggressive hematologic malignancies. We describe herein an exploration of novel Akt inhibitors for cancer therapy through structural optimization of previously described 4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives. Our studies yielded a novel series of pyrrolopyrimidine based phenylpiperidine carboxamides capable of potent inhibition of Akt1. Notably, 10h exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 10h induced cell apoptosis and cell cycle arrest in G2/M phase, and significantly downregulated the phosphorylation of Akt downstream effectors GSK3ß and S6 in Jeko-1 cells.