Small molecules as modulators of the proteostasis machinery: Implication in cardiovascular diseases.

With the escalating prevalence of cardiovascular diseases, the substantial socioeconomic burden on healthcare systems is intensifying. Accumulating empirical evidence underscores the pivotal role of the proteostasis network in regulating cardiac homeostasis and function. Disruptions in proteostasis may contribute to the loss of protein function or the acquisition of toxic functions, which are intricately linked to the development of cardiovascular ailments such as atrial fibrillation, heart failure, atherosclerosis, and cardiac aging.

Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer.

A group of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, A14 was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of A14 improved by 4-6-fold (IC < 10 nM), indicating its hypoxia-selectivity.

Chemoproteomics reveals arctigenin as a phagophore-closure blocker via targeting ESCRT-I subunit VPS28.

Arctigenin is the active ingredient of the traditional medicines Arctium lappa and Fructus Arctii and has been extensively investigated for its diverse pharmacological functions, including its novel anti-austerity activity. Although several mechanisms have been proposed, the direct target of arctigenin to induce anti-austerity activity remains unclear. In this study, we designed and synthesized photo-crosslinkable arctigenin probes and utilized them in the chemoproteomic profiling of potential target proteins directly in living cells.

Design, synthesis and biological evaluation of the tumor hypoxia-activated PROTACs bearing caged CRBN E3 ligase ligands.

Tumor hypoxia-activated proteolysis targeting chimeras (ha-PROTACs) 9 and 10 were designed and synthesized by incorporating the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4‑nitrobenzyl into the structure of the cereblon (CRBN) E3 ligand of an epidermal growth factor receptor 19 deletions (EGFR-based PROTAC 8. The in vitro protein degradation assay demonstrated that 9 and 10 could effectively and selectively degrade EGFR in tumor hypoxia. Meanwhile, these two compounds showed higher potency in inhibiting cell viability and migration, as well as in promoting cells apoptosis in tumor hypoxia.

Design, synthesis and biological evaluation of novel tumor hypoxia-activated EGFR tyrosine kinase inhibitors.

Hypoxia is widespread in solid tumors, such as NSCLC, and has become a very attractive target. On the basis of AZD9291 scaffold, novel hypoxia-targeted EGFR inhibitors without the acrylamide warhead but containing hypoxic reductive activation groups were described. Among them, compound JT21 exhibited impressive inhibitory activity (IC = 23 nM) against EGFR and displayed about 21-fold inhibitory activity decrease against EGFR.

Design, Synthesis, and Biological Evaluation of 2-Anilino-4-Triazolpyrimidine Derivatives as CDK4/HDACs Inhibitors.

Purpose: To enhance the cytotoxicities of our obtained CDK4 inhibitors and get CDK4/HDACs inhibitors with potent enzymatic inhibitory and anti-proliferative activities.

Methods: A series of novel CDK4/HDACs inhibitors were designed and synthesized by incorporating the HDAC pharmacophores (hydroxylamine or o-diaminoaniline) into the basic structure of our newly obtained 2-anilino-4-triazolpyrimidine based CDK4 inhibitors. The enzymatic inhibitory (HDAC1, CDK2, CDK4, and CDK6) activities and cytotoxicities of these compounds were evaluated.

Development of hypoxia-activated PROTAC exerting a more potent effect in tumor hypoxia than in normoxia.

Hypoxia is a hallmark of many solid tumors, and it causes the overexpression of a variety of proteins including the epidermal growth factor receptor (EGFR). Many antitumor prodrugs have been designed to target hypoxia. Here we report the identification of a kind of hypoxia-activated proteolysis targeting chimera (ha-PROTAC) by introducing the hypoxia-activated leaving group (1-methyl-2-nitro-1-imidazol-5-yl)methyl or 4-nitrobenzyl into the structure of an EGFR-based PROTAC.

Pharmacokinetics, Urinary Excretion, and Pharmaco-Metabolomic Study of Tebipenem Pivoxil Granules After Single Escalating Oral Dose in Healthy Chinese Volunteers.

Tebipenem pivoxil (TBPM-PI), an oral carbapenem antibiotic, has shown special advantages in pediatric infections and was in urgent need in China. Although pharmacokinetics, urinary excretion, and metabolite information of its active form tebipenem (TBPM) has been reported, ethnic differences may exist among the Chinese and Japanese population. By now, no systematic pharmacokinetics, urinary excretion, metabolites, or safety information has been revealed to the Chinese population.

Design, synthesis, and biological study of 4-[(2-nitroimidazole-1-alkyloxyl)aniline]-quinazolines as EGFR inhibitors exerting cytotoxicities both under normoxia and hypoxia.

Purpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia.

Methods: A series of 4-[(2-nitroimidazole-1-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound.

An overview of recent progress in siderophore-antibiotic conjugates.

Multi-drug resistant infections caused by Gram-negative bacteria have become one of the most important reasons for the failure of clinical anti-infective treatment. Siderophore-antibiotic conjugates, which were designed based on a "Trojan horse" strategy wherein features enabled active uptake to bypass the Gram-negative cell wall, have been expected to be a weapon for anti-infective treatment in the clinic. Herein, we review antibiotic drug design strategies based on mimics of nature siderophores reported in recent years, we also focus our attention on the relationship between the type of linker and the corresponding antibacterial activity.

CDK11 plays a critical role in the tumorigenicity of esophageal squamous cell carcinoma cells and is a potential drug target.

Esophageal squamous cell carcinoma (ESCC) is a serious malignancy with limited options for targeted therapy. The exploration of novel targeted therapies for combating ESCC is urgently needed. Cyclin-dependent kinases (CDKs) play important roles in the progression of cancers; however, the function of CDK11 (cyclin-dependent kinase 11) in ESCC is still unknown.

Recent development of CDK inhibitors: An overview of CDK/inhibitor co-crystal structures.

The cyclin-dependent protein kinases (CDKs) are protein-serine/threonine kinases that display crucial effects in regulation of cell cycle and transcription. While the excessive expression of CDKs is intimate related to the development of diseases including cancers, which provides opportunities for disease treatment. A large number of small molecules are explored targeting CDKs.

Recent Development of Oridonin Derivatives with Diverse Pharmacological Activities.

Oridonin is one of the major components isolated from Isodon rubescens, a traditional Chinese medicine, and it has been confirmed to exhibit many kinds of biological activities including anticancer, anti-inflammation, antibacterial and so on. However, the poor pharmaceutical property limits the clinical applications of oridonin. So many strategies have been explored in the purpose of improving the potencies of oridonin, and structure modification is one thus way.

An overview of the binding models of FGFR tyrosine kinases in complex with small molecule inhibitors.

The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors.

Development of the Third Generation EGFR Tyrosine Kinase Inhibitors for Anticancer Therapy.

Epidermal growth factor receptor (EGFR) is one of the most important targets in anticancer therapy. Till date, a large number of first and second generation EGFR tyrosine kinase inhibitors (TKIs) have been marketed or advanced into clinical studies. However, the occurrence of TKI-resistant mutations has led to the loss of efficacy of these inhibitors.

Identification of novel 4-anilinoquinazoline derivatives as potent EGFR inhibitors both under normoxia and hypoxia.

A novel series of 4-anilinoquinazoline derivatives (19a-19t) were designed and synthesized through incorporation of the 2-nitroimidazole moiety into the 4-anilinoquinazoline scaffold of EGFR inhibitors. The most promising compound 19h displayed potent EGFR inhibitory activity with the IC50 value of 0.47 nM.

Design, synthesis and biological evaluation of 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazolines as efficient EGFR inhibitors exerting cytotoxic effects both under normoxia and hypoxia.

A series of novel 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazoline derivatives (15a-15r) were designed, synthesized and evaluated as efficient EGFR inhibitors through introduction of hypoxia activated nitroimidazole moiety into the quinazoline scaffold of EGFR inhibitors. The majority of these newly synthesized compounds exhibited comparable EGFR inhibitory activities to gefitinib and moderate to excellent anti-proliferative activities against HT-29 cells under normoxia and hypoxia. The most promising compound 15c displayed the IC50 value of 0.

Development of EGFR family small molecule inhibitors for anticancer intervention: an overview of approved drugs and clinical candidates.

The epidermal growth factor receptor (EGFR) family includes four structurally related receptor tyrosine kinases, termed as HER1 (EGFR, erbB1), HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). Given its intimate role in the development of several solid tumors, excessive HER signaling provides a unique opportunity for anticancer intervention. Along with extensive pharmacological studies validating the therapeutic potential of targeting the EGFR family for cancer therapy, kinase inhibitors of this family are continuously coming up and entering clinical studies.

N-Benzyl-6-de-oxy-3,6-imino-methyl-ene-1,2,3,5-O-tetra-acetyl-α-d-1(S)-epiallo-furan-ose.

The mol-ecule of the title compound, C(22)H(27)NO(9), an azasugar derivative, consists of one benzene ring and two fused rings, which have the cis arrangement at the ring junctions, and gives a V-shaped geometry. The inter-planar angle between the five- and six-membered rings is 65.69 (11)°.

1,2;5,6-Di-O-isopropyl-idene-3-C-nitro-methyl-α-d-allofuran-ose.

The mol-ecule of the title compound, C(13)H(21)NO(8), consists of two methyl-enedi-oxy rings and one tetra-hydro-furan ring. In the crystal, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into helical chains running along the 6(1) screw axis. Weak inter-molecular C-H⋯O hydrogen bonds help to stabilize the crystal packing.