Functional Hexafluoroisopropyl Group Used in the Construction of Biologically Important Pyrimidine Derivatives.

A series of versatile 4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)pyridine intermediates have been developed to efficiently produce biaryls, amines, ethers, and thioethers. These hydrolysis-stable ether intermediates exhibit reactivity toward electron-donating groups and nucleophiles in cross-coupling and nucleophilic substitution reactions while surpassing the stability of corresponding aryl halides. In comparison to conventional coupling methods, this protocol offers an alternative pathway for accessing natural product and drug-like compounds without the need for metal catalysts.

Discovery of Novel [1,2,4]Triazolo[1,5-]pyrimidine Derivatives as Novel Potent S-Phase Kinase-Associated Protein 2 (SKP2) Inhibitors for the Treatment of Cancer.

Skp1-CUL1-ROC1-F-box E3 ubiquitin ligases' main component S-phase kinase-associated protein 2 (Skp2) is responsible for specifically recognizing ubiquitination-modified substrates to be degraded such as p27 and p21 in the case of binding with adaptor protein Cks1. Pharmacological inhibition of Skp2 has exhibited promising antitumor activity. Herein, we present the design and optimization of a series of [1,2,4]triazolo[1,5-]pyrimidine-based small molecules targeting Skp2.

Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer.

LSD1 (histone lysine-specific demethylase 1) has been gradually disclosed to act as an immunomodulator to enhance antitumor immune response. Despite the identification of numerous potent LSD1 inhibitors, there remains a lack of LSD1 inhibitors approved for marketing. Novel LSD1 inhibitors with different mechanisms are therefore needed.

The mechanism of action and chemical synthesis of FDA newly approved drug molecules.

In 2023, the U.S. Food and Drug Administration has approved 29 small molecule drugs.

Discovery of TK-642 as a highly potent, selective, orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2 IC = 2.7 nmol/L) with favorable pharmacokinetic profiles ( = 42.

The recent advance and prospect of poly(ADP-ribose) polymerase inhibitors for the treatment of cancer.

Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long-term medication-induced drug resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP-DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first-line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application.

Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling.

DCN1, a critical co-E3 ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. (IC= 2.

Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as potent reversal agents against ABCB1-mediated multidrug resistance.

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 μM (IC = 27.

A comprehensive review of new small molecule drugs approved by the FDA in 2022: Advance and prospect.

In 2022, the U.S. Food and Drug Administration approved a total of 16 marketing applications for small molecule drugs, which not only provided dominant scaffolds but also introduced novel mechanisms of action and clinical indications.

A comprehensive review of small molecule drugs approved by the FDA in 2023: Advances and prospects.

In 2023, the U.S. Food and Drug Administration has approved 55 novel medications, consisting of 17 biologics license applications and 38 new molecular entities.

Histone deacetylase complexes: Structure, regulation and function.

Histone deacetylases (HDACs) are key epigenetic regulators, and transcriptional complexes with deacetylase function are among the epigenetic corepressor complexes in the nucleus that target the epigenome. HDAC-bearing corepressor complexes such as the Sin3 complex, NuRD complex, CoREST complex, and SMRT/NCoR complex are common in biological systems. These complexes activate the otherwise inactive HDACs in a solitary state.

Decoding CLU (Clusterin): Conquering cancer treatment resistance and immunological barriers.

One major obstacle in the treatment of cancer is the presence of proteins resistant to cancer therapy, which can impede the effectiveness of traditional approaches such as radiation and chemotherapy. This resistance can lead to disease progression and cause treatment failure. Extensive research is currently focused on studying these proteins to create tailored treatments that can circumvent resistance mechanisms.

Mass spectrometry-based pseudotargeted metabolomics reveals metabolic variations in a2-induced gastric cancer cell.

Gastric cancer (GC) is one of the most malignant tumors with high morbidity and mortality in the world. Compound , a Jiyuan oridonin derivative, exhibited excellent anti-proliferative activity against GC cells. To investigate the gastric cellular response to therapy as a novel drug candidate, we adopted a pseudotargeted metabolomics method to explore metabolic variation in -induced MGC-803 gastric cells using liquid chromatography tandem mass spectrometry combined with multivariate statistical analysis.

CD155 as an emerging target in tumor immunotherapy.

CD155 is an immunoglobulin-like protein overexpressed in almost all the tumor cells, which not only promotes proliferation, adhesion, invasion, and migration of tumor cells, but also regulates immune responses by interacting with TIGIT, CD226 or CD96 receptors expressed on several immune cells, thereby modulating the functionality of these cellular subsets. As a novel immune checkpoint, the inhibition of CD155/TIGIT, either as a standalone treatment or in conjunction with other immune checkpoint inhibitors, has demonstrated efficacy in managing advanced solid malignancies. In this review, we summarize the intricate relationship between on tumor surface CD155 and its receptors, with further discussion on how they regulate the occurrence of tumor immune escape.

USP7 as an emerging therapeutic target: A key regulator of protein homeostasis.

Maintaining protein balance within a cell is essential for proper cellular function, and disruptions in the ubiquitin-proteasome pathway, which is responsible for degrading and recycling unnecessary or damaged proteins, can lead to various diseases. Deubiquitinating enzymes play a vital role in regulating protein homeostasis by removing ubiquitin chains from substrate proteins, thereby controlling important cellular processes, such as apoptosis and DNA repair. Among these enzymes, ubiquitin-specific protease 7 (USP7) is of particular interest.

Discovery of neddylation E2s inhibitors with therapeutic activity.

Neddylation is the writing of monomers or polymers of neural precursor cells expressed developmentally down-regulated 8 (NEDD8) to substrate. For neddylation to occur, three enzymes are required: activators (E1), conjugators (E2), and ligators (E3). However, the central role is played by the ubiquitin-conjugating enzymes E2M (UBE2M) and E2F (UBE2F), which are part of the E2 enzyme family.

Neddylation-dependent LSD1 destabilization inhibits the stemness and chemoresistance of gastric cancer.

Histone lysine-specific demethylase 1 (LSD1) expression has been evaluated in multiple tumors, including gastric cancer (GC). However, the mechanisms underlying LSD1 dysregulation in GC remain largely unclear. In this study, neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) was identified to be conjugated to LSD1 at K63 by ubiquitin-conjugating enzyme E2 M (UBE2M), and this neddylated LSD1 could promote LSD1 ubiquitination and degradation, leading to a decrease of GC cell stemness and chemoresistance.

Micafungin: A promising inhibitor of UBE2M in cancer cell growth suppression.

Neddylation is a protein modification process similar to ubiquitination, carried out through a series of activating (E1), conjugating (E2), and ligating (E3) enzymes. This process has been found to be overactive in various cancers, leading to increased oncogenic activities. Ubiquitin-conjugating enzyme 2 M (UBE2M) is one of two neddylation enzymes that play a vital role in this pathway.

Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer.

Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC value of 13 nM, about 4.

LSD1: an emerging face in altering the tumor microenvironment and enhancing immune checkpoint therapy.

Dysregulation of various cells in the tumor microenvironment (TME) causes immunosuppressive functions and aggressive tumor growth. In combination with immune checkpoint blockade (ICB), epigenetic modification-targeted drugs are emerging as attractive cancer treatments. Lysine-specific demethylase 1 (LSD1) is a protein that modifies histone and non-histone proteins and is known to influence a wide variety of physiological processes.

The recent advance of Interleukin-1 receptor associated kinase 4 inhibitors for the treatment of inflammation and related diseases.

The interleukin-1 receptor associated kinase 4 (IRAK-4) is a member of serine-threonine kinase family, which plays an important role in the regulation of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs) related signaling pathways. At present, the IRAK-4 mediated inflammation and related signaling pathways contribute to inflammation, which are also responsible for other autoimmune diseases and drug resistance in cancers. Therefore, targeting IRAK-4 to develop single-target, multi-target inhibitors and proteolysis-targeting chimera (PROTAC) degraders is an important direction for the treatment of inflammation and related diseases.