Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective.

The key proteins involved in transcriptional regulation play convergent roles in cellular homeostasis, and their dysfunction mediates aberrant gene expressions that underline the hallmarks of tumorigenesis. As tumor progression is dependent on such abnormal regulation of transcription, it is important to discover novel chemical entities as antitumor drugs that target key tumor-associated proteins involved in transcriptional regulation. Despite most key proteins (especially transcription factors) involved in transcriptional regulation are historically recognized as undruggable targets, multiple targeting approaches at diverse levels of transcriptional regulation, such as epigenetic intervention, inhibition of DNA-binding of transcriptional factors, and inhibition of the protein-protein interactions (PPIs), have been established in preclinically or clinically studies. In addition, several new approaches have recently been described, such as targeting proteasomal degradation and eliciting synthetic lethality. This review will emphasize on accentuating these developing therapeutic approaches and provide a thorough conspectus of the drug development to target key proteins involved in transcriptional regulation and their impact on future oncotherapy.

A hybrid of thiazolidinone with the hydroxamate scaffold for developing novel histone deacetylase inhibitors with antitumor activities.

A series of novel histone deacetylase (HDAC) inhibitors were designed, synthesized and evaluated based on the strategies of a hybrid of the classic pharmacophore of HDAC inhibitors with the thiazolidinone scaffold. Some of the compounds 12i showed potent HDAC1 inhibition with nM IC50 values, more importantly, compound displayed much better anti-metastatic effects than vorinostat (SAHA) against migration of the A549 cell line. Further mechanism exploration implied that compound 12i may inhibit tumor metastasis via modulating the epithelial-mesenchymal transition (EMT) and upregulating the acetylation of α-tubulin.

Rapid Synthesis of Functions-Integrated Hydrogel as a Self-Powered Wound Dressing for Real-Time Drug Release and Health Monitoring.

A bio-hydrogel is prepared via a low-cost and time-saving strategy and is studied as a self-powered wound dressing for precision medicine and health monitoring. Promoted by a dual self-catalytic pair composed of Fe3+ and catechol, gelation time is dramatically accelerated to 15 s and the hydrogel can be freely modeled at -18 °C without losing flexibility. As smart wound dressing, the required properties such as self-healing, self-adhesion, antibacterial, and sensing stability, are integrated into one hydrogel. TA@CNC offers abundant hydrogen bond and metal-ligand coordination which facilitate the hydrogel with a self-healing efficiency of 91.6%. Owing to the catechol in TA@CNC, hydrogel can adhere to multiple substrates including skin, and show good antibacterial activity. Inspired by a fruit battery, a self-powered wound dressing is fabricated, which exhibits excellent correlation and efficiency in real-time monitoring of body activity and drug release. In vivo experiments prove that efficient drug release of hydrogel dressing significantly accelerate wound healing. Additionally, the dressing exhibits excellent biocompatibility and has no negative impacts on organs. Herein, a smart wound dressing that is different from the traditional way is proposed. As a self-powered device, it can be integrated with wireless devices and is expected to participate in promising applications.

Discovery of a Potent and Oral Available Complex I OXPHOS Inhibitor That Abrogates Tumor Growth and Circumvents MEKi Resistance.

Targeting oxidative phosphorylation (OXPHOS) has emerged as a promising therapeutic strategy for cancer therapy. Here, we discovered a 1H-1,2,3-triazole derivative HP661 as a highly potent and orally available OXPHOS inhibitor that effectively blocked the activity of mitochondrial complex I. HP661 specifically compromised the mitochondrial oxygen consumption of high-OXPHOS lung cancer cells but not that of low-OXPHOS lung cancer cells or normal cells in the low nanomolar range. Notably, mitogen-activated protein kinase kinase (MEK) inhibitor (trametinib)-resistant lung cancer cells with high levels of OXPHOS also showed marked sensitivity to HP661, as indicated by decreased clonogenic growth and increased cell apoptosis upon treatment. In a mouse model of high-OXPHOS lung cancer, HP661 treatment not only significantly suppressed tumor growth but also augmented the therapeutic efficacy of trametinib by impairing tumor mitochondrial respiration. In summary, we identified HP661 as a highly effective OXPHOS inhibitor to abrogate the growth of high OXPHOS-dependent tumors and conquer high OXPHOS-mediated drug resistance.

Discovery of a Highly Potent and Selective MYOF Inhibitor with Improved Water Solubility for the Treatment of Gastric Cancer.

Myoferlin (MYOF) mediates the growth and metastasis of various cancers as an emerging therapeutic target by regulating exocytosis and endocytosis. However, the previously reported MYOF inhibitor, 6y, failed to be a favorable candidate agent due to its poor physicochemical properties, such as water solubility, in preclinical studies. Naturally, a novel range of MYOF inhibitors was synthesized and optimized based on the lead compound 6y. The optimal compound HJ445A potently repressed the proliferation of gastric cancer cells with IC50 values of 0.16 and 0.14 µM in MGC803 and MKN45, respectively. Moreover, HJ445A bound to the MYOF-C2D domain with a KD of 0.17 µM, and HJ445A prevented the migration of gastric cancer cells by reversing the epithelial-mesenchymal transition (EMT) process and inhibited the colony formation of the MKN45 cells in a concentration-dependent manner. Notably, the water solubility of HJ445A was significantly improved compared to 6y, with about 170-fold enhancement. Additionally, HJ445A also demonstrated superior antitumor efficacy in vivo.

Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuole-presenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides a basis for the future progress of more small molecules for TNBC treatment.

Discovery of 2-Amino-3-cyanothiophene Derivatives as Potent STAT3 Inhibitors for the Treatment of Osteosarcoma Growth and Metastasis.

Osteosarcoma is one of the most common malignant bone tumors. However, the treatment and clinical outcomes of osteosarcoma have hardly changed over the past three decades due to the comprehensive heterogeneity and higher rate of mutation of osteosarcoma. Recent studies have shown that STAT3 has the potential to suppress the proliferation and metastasis of osteosarcoma. In this study, a novel class of 2-amino-3-cyanothiophene derivatives were designed and synthesized to inhibit osteosarcoma by targeting STAT3. Representative compound 6f showed potent antiproliferative effects against osteosarcoma cells, directly bound to the STAT3 SH2 domain with a KD of 0.46 µM, and inhibited the phosphorylation of STAT3 Y705 in a dose-dependent manner. Furthermore, compound 6f promoted osteosarcoma cell apoptosis in vitro and significantly suppressed the growth and metastasis of osteosarcoma in vivo. These findings demonstrate that targeting STAT3 may be a feasible therapeutic strategy for the treatment of metastatic osteosarcoma.

Discovery of a Novel Potent STAT3 Inhibitor HP590 with Dual p-Tyr705/Ser727 Inhibitory Activity for Gastric Cancer Treatment.

Accumulating evidence has documented that STAT3 phosphorylation at Tyr705 and Ser727 jointly promotes the initiation and progression of gastric cancer. However, most reported STAT3 inhibitors have mainly focused on suppressing STAT3 phosphorylation at Tyr705 while ignoring the tumorigenic effects of phosphorylation at Ser727. Herein, we described the design, synthesis, and structure-activity relationship studies on a series of triaromatic heterocyclic derivatives as potent dual phosphorylation STAT3 inhibitors. These efforts led to the discovery of the best compound 3h (HP590) among the investigated ones, a novel, highly potent, and orally bioavailable STAT3 inhibitor possessing lower nanomolar inhibitory activity toward p-Tyr705 and p-Ser727. Target validation revealed that HP590 selectively targets STAT3 to remarkably inhibit its canonical and noncanonical activation and corresponding biological functions, thereby resulting in the growth inhibition of gastric cancer in vitro and in vivo, highlighting the therapeutic potential of dual phosphorylation STAT3 inhibitors for gastric cancer.

An Emerging Therapeutic Approach by Targeting Myoferlin (MYOF) for Malignant Tumors.

Myoferlin (MYOF), as a member of the ferlin family, is a type II transmembrane protein with a single transmembrane domain at the carbon terminus. Studies have shown that MYOF is involved in pivotal physiological functions related to numerous cell membranes, such as extracellular secretion, endocytosis cycle, vesicle trafficking, membrane repair, membrane receptor recycling, and secreted protein efflux. Recently, the studies have also revealed that MYOF is overexpressed in a variety of cancers such as colorectal cancer, pancreatic cancer, breast cancer, melanoma, gastric cancer, and non-small-cell lung cancer. High expression of MYOF is associated with the high invasion of tumors and poor clinical prognosis. MYOF medicates the expression, secretion, and distribution of proteins, which were closely related to cancers, as well as the energy utilization of cancer cells, lipid metabolism and other physiological activities by regulating the physiological processes of membrane transport. In this short article, we briefly summarize the latest progress related to MYOF, indicating that small molecule inhibitors targeting the MYOF-C2D domain can selectively inhibit the proliferation and migration of cancer cells, and MYOF may be a promising target for the treatment of malignant tumors.

Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery.

Curing malignant carcinomas is a grand ambition in the development of human health. Over the past decades, targeted therapies have become one of the most successful ways of achieving this. Of these approaches, small molecule inhibitors and monoclonal antibodies are two major methods, however several barriers to their development and clinical use still exist. The use of proteolysis-targeting chimeras (PROTACs) is a new technology through utilizing a intracellular ubiquitin-proteasome system to induce targeted protein degradation, is receiving much attention in the field of targeted therapies. Hetero-bifunctional PROTACs have the potential to eliminate the "undruggable" proteome that comprises about 85% of human proteins, which indicates their great prospects in therapeutic fields. However, there are some hurdles preventing current PROTACs moving from bench to clinic, such as delivery and bioavailability. This review provides an overview of the development of PROTAC technology and will briefly summarize the future possible directions of this approach.

Discovery of potent ureido tetrahydrocarbazole derivatives for cancer treatments through targeting tumor-associated macrophages.

Tumor-associated macrophages (TAMs) are one of the prominent components of the tumor microenvironment (TME). The polarization peculiarity of TAMs drives them to infiltrate and active with states between M1 (anti-tumor) and M2 (pro-tumor) phenotypes in cancers. Exploiting small molecular drugs through targeting TAMs to repolarize them into an antitumor phenotype is considered as a novel strategy for cancer treatments in recent years. For discovering novel compounds that target TAMs, a series of ureido tetrahydrocarbazole derivatives were designed, synthesized and evaluated both in vitro and in vivo. Among them, compound 23a was found to dose-dependently repolarize TAMs from M2 to M1 both in vitro and in vivo. And more importantly, the in vivo experiments also revealed that compound 23a was capable of remarkably inhibiting tumor growth of the LLC mouse model. Moreover, the synergy of compound 23a with anti-PD-1 antibody had more superior antineoplastic effects than the exclusive use of either in vivo.

Discovery and Optimization of N-Substituted 2-(4-pyridinyl)thiazole carboxamides against Tumor Growth through Regulating Angiogenesis Signaling Pathways.

Inhibition of angiogenesis is considered as one of the desirable pathways for the treatment of tumor growth and metastasis. Herein we demonstrated that a series of pyridinyl-thiazolyl carboxamide derivatives were designed, synthesized and examined against angiogenesis through a colony formation and migration assays of human umbilical vein endothelial cells (HUVECs) in vitro. A structure-activity relationship (SAR) study was carried out and optimization toward this series of compounds resulted in the discovery of N-(3-methoxyphenyl)-4-methyl-2-(2-propyl-4-pyridinyl)thiazole-5-carboxamide (3k). The results indicated that compound 3k showed similar or better effects compared to Vandetanib in suppressing HUVECs colony formation and migration as well as VEGF-induced angiogenesis in the aortic ring spreading model and chick embryo chorioallantoic membrane (CAM) model. More importantly, compound 3k also strongly blocked tumor growth with the dosage of 30 mg/kg/day, and subsequent mechanism exploration suggested that this series of compounds took effect mainly through angiogenesis signaling pathways. Together, these results suggested compound 3k may serve as a lead for a novel class of angiogenesis inhibitors for cancer treatments.

Synthesis and biological evaluation of novel tetrahydro-ß-carboline derivatives as antitumor growth and metastasis agents through inhibiting the transforming growth factor-ß signaling pathway.

The transforming growth factor beta (TGFß) signaling cascade is considered as one of the pivotal oncogenic pathways in most advanced cancers. Inhibition of the TGFß signaling pathway by specific antagonists, neutralizing antibodies, or small molecules is considered as an effective strategy for the treatment of tumor growth and metastasis. Here we demonstrated the identification of a series of tetrahydro-ß-carboline derivatives from virtual screening which potentially inhibit the TGFß signaling pathway. Optimization of the initial hit compound 2-benzoyl-1,3,4,9-tetrahydro-ß-carboline (8a) through substitution at different positions to define the structure-activity relationship resulted in the discovery of potent inhibitors of the TGFß signaling pathway. Among them, compound 8d, one of the tested compounds, not only showed potent inhibition of lung cancer cell proliferation and migration in vitro but also strongly suppressed growth of lung cancer and breast cancer in vivo.