Macrocyclic Neutralizer to Polybrene via Direct Host-Guest Complexation.

Hexadimethrine bromide (HB), a synthetic polycationic species, was introduced to clinical practice as a heparin antidote and recently used in gene therapy. However, HB causes various complications such as severe red blood cells (RBCs) aggregation and tissue damage. Herein, we have synthesized a water-soluble quaterphen[3]arene containing multiple sulfonate moieties (SQP3) as a novel macrocyclic neutralizer to reverse HB via direct host-guest complexation. SQP3 exhibited a robust binding affinity toward HB with a considerably high association constant of (4.73 ± 0.61) × 107 M-1. Co-dosed with 1 equiv of SQP3, HB-induced RBCs aggregation and blood coagulation could be effectively reversed. In vitro cellular assay verified that complexation of HB with SQP3 significantly decreased reactive oxygen species production, thereby suppressing cell apoptosis. In vivo neutralization efficacy studies demonstrated that HB/SQP3 was capable of alleviating related organic damage caused by HB and improving the survival rate of HB-treated mice from 20 to 100%.

Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Screening of efficient salicylaldoxime reactivators for DFP and paraoxon-inhibited acetylcholinesterase.

Previously we reported two salicylaldoxime conjugates (L7R3 and L7R5) showing equal or even higher reactivating efficiency for both organophosphorus nerve agent and pesticide inhibited acetylcholinesterase in comparison to obidoxime and HI-6. In this study, L7R3 and L7R5 were selected as lead compounds and refined by employing a fragment-based drug design strategy, and a total of 32 novel salicylaldoxime conjugates were constructed and screened for DFP and paraoxon inhibited acetylcholinesterase. The findings demonstrate that the conjugate L73R3, which contains a 4-nitrophenyl group, exhibited a higher reactivation efficacy against paraoxon-inhibited acetylcholinesterase compared to obidoxime and HI-6. It was confirmed that the combination of a 4-pyridinyl or 4-nitrophenyl peripheral site ligand, a piperazine linker and a methyl or chloro-substituted salicylaldoxime could construct efficient nonquaternary oxime reactivators. The results hold promise for developing a new generation of highly effective antidotes for organophosphate poisoning.

Novel Scaffold Agonists of the α2A Adrenergic Receptor Identified via Ensemble-Based Strategy.

The α2A adrenergic receptor (α2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α2A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α2A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α2A-AR agonists with novel scaffold. Our results showed that compounds SY-15 and SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 µM concentrations of SY-15 and SY-17, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of SY-15 and SY-17 with the α2A-AR. The binding free energies of SY-15 and SY-17 calculated by MD simulations were -45.93 and -71.97 kcal/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics.

The next generation of EGFR inhibitors: a patenting perspective of PROTACs based EGFR degraders.

INTRODUCTION: Abnormal expression of epidermal growth factor receptor (EGFR) contributes to tumor development, especially in non-small cell lung cancer (NSCLC). Although multiple inhibitors have been developed to target diverse EGFR mutations and several have been approved, the inevitable drug resistance and side effect remain a challenge, which motivates novel strategies. Proteolysis-targeting chimeras (PROTACs) have been gaining momentum for their potential as novel therapeutics for human diseases by triggering protein degradation. To date, various potent and specific EGFR PROTACs have been discovered and some of them have entered clinical trials. AREAS COVERED: This review provides an overview of EGFR degraders in patents from 2016 to 2022. It provides an update of the discovery strategies, chemical structures, and molecular profiling of all available EGFR PROTACs. SciFinder, PubMed, Web of Science, EPO, and CNIPA databases were used for searching the literature and patents for EGFR PROTACs. EXPERT OPINION: By employing the PROTAC technology, highly potent and selective EGFR degraders based on four generation EGFR inhibitors have been developed, which offer a new strategy to target EGFR mutations and overcome the drug resistance. Despite the satisfactory result in vitro and in vivo studies, their therapeutic value awaits more rigorous preclinical testing and clinical investigation.

Selective Fluorescent Sensing for Iron in Aqueous Solution by A Novel Functionalized Pillar[5]arene.

Iron ion is one of the most physiologically important elements in metabolic processes, indispensable for all living systems. Since its excess can lead to severe diseases, new approaches for its monitoring in water samples are urgently needed to meet requirements. Here, we firstly report a novel and universal route for the synthesis of a series of pillar[n]arene derivates containing one benzoquinone unit by photocatalysis. With this in hand, an anthracene - appended water - soluble pillar[5]arene (H) with excellent fluorescence sensing potency was prepared. H enabled the ultrasensitive detection of iron ions in aqueous solution with limits of detection of 10-8  M. Over a wide range of metal ions, H exhibited specific selectivity toward Fe3+ . More importantly, H could still properly operate in a simulated sewage sample, coexisting with multiple interference ions.

Discovery of highly potent and selective KRASG12C degraders by VHL-recruiting PROTACs for the treatment of tumors with KRASG12C-Mutation.

Although several covalent KRASG12C inhibitors have made great progress in the treatment of KRASG12C-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRASG12C Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRASG12C-dependent cancer cells growth with nanomolar IC50 and DC50 values, and ＞ 95 % maximum degradation (Dmax). Molecular dynamics (MD) simulation showed that YN14 induced a stable KRASG12C: YN14: VHL ternary complex with low binding free energy (ΔG). Notably, YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model with well-tolerated dose-schedules. We also found that KRASG12C degradation exhibited advantages in overcoming adaptive KRASG12C feedback resistance over KRASG12C inhibition. Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRASG12C-mutant cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRASG12C-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination.

Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations.

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC50 values and achieved picomolar DC50 values and >99% of maximum degradation (Dmax) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-METY1230H and c-METD1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

Discovery of Highly Potent CRBN Ligands and Insight into Their Binding Mode through Molecular Docking and Molecular Dynamics Simulations.

Cereblon (CRBN) is a substrate receptor of E3 ubiquitin ligase as well as the target of thalidomide and lenalidomide, plays a vital role in endogenous protein degradation. In this article, two series of compounds with novel structure were designed, synthesized and evaluated against CRBN. YJ1b, designed based on our previous finding, shown strong binding affinity toward CRBN (IC50 =0.206 µM) by forming a salt bridge interaction with amino acid residue Glu377 of CRBN, it was 13-fold compared with that of lenalidomide (IC50 =2.694 µM) in TR-FRET assay. YJ2c and YJ2h, two analogs of YJ1b, also exhibit high binding affinity toward CRBN (IC50 =0.211 µM and IC50 =0.282 µM, respectively). While, molecular docking and 100 ns molecular dynamic simulation studies were conducted to insight into the unique binding mode of YJ1b, YJ2c and YJ2e toward CRBN. The new compounds with special binding mode in this article may serve for the further optimization and discovery of novel high potent CRBN ligands.

Discovery and pharmacological characterization of a novel benzimidazole TRPV4 antagonist with cyanocyclobutyl moiety.

GSK-Bz, a TPRV4 antagonist discovered by GSK, displayed potent in vitro TRPV4 inhibition activity, and demonstrated ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. In this study, a series of GSK-Bz derivatives were designed and synthesized based on our previous findings. Compound 2b with cyanocyclobutyl moiety (IC50 = 22.65 nM) was found to be 5.3-fold more potent than GSK-Bz (IC50 = 121.6 nM) in the calcium imaging experiment. Patch-clamp experiments confirmed that compound 2b (IR = 77.1%) also gave significantly improved potency on TRPV4 currents measured at -60 mV. Furthermore, 2b effectively suppressed the permeability response to LPS in HUVEC with negligible cytotoxicity (CC50 > 100 µM). The in vivo protective effects of compounds 2b on acute lung injury were finally assessed in an LPS-induced ALI mice model. Notably, 2b gave better results than HC-067047 against all of the tested indexes (lung W/D ratios, the concentrations of BALF protein and pathological scores), indicating that 2b is a novel and highly potent TRPV4 antagonist which is worth for further development. Currently, evaluation for the drug-like properties of 2b is underway.

A Biocompatible Liquid Pillar[n]arene-Based Drug Reservoir for Topical Drug Delivery.

Advanced external preparations that possess a sustained-release effect and integrate few irritant elements are urgently needed to satisfy the special requirements of topical administration in the clinic. Here, a series of liquid pillar[n]arene-bearing varying-length oligoethylene oxide chains (OEPns) were designed and synthesized. Following rheological property and biocompatibility investigations, pillar[6]arene with triethylene oxide substituents (TEP6) with satisfactory cavity size were screened as optimal candidate compounds. Then, a supramolecular liquid reservoir was constructed from host-guest complexes between TEP6 and econazole nitrate (ECN), an external antimicrobial agent without additional solvents. In vitro drug-release studies revealed that complexation by TEP6 could regulate the release rate of ECN and afford effective cumulative amounts. In vivo pharmacodynamic studies confirmed the formation of a supramolecular liquid reservoir contributed to the accelerated healing rate of a S. aureus-infected mouse wound model. Overall, these findings have provided the first insights into the construction of a supramolecular liquid reservoir for topical administration.

Inhibition of cannabinoid receptor type 1 sensitizes triple-negative breast cancer cells to ferroptosis via regulating fatty acid metabolism.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that displays highly aggressive with poor prognosis. Owing to the limited targets and drugs for TNBC clinical therapy, it is necessary to investigate the factors regulating cancer progression and develop novel therapies for cancer treatment. Ferroptosis, a nonapoptotic form of programmed cell death characterized by accumulation of iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various cancer-related signaling pathways. Recently, considerable progress has been made in demonstrating the critical role of lipid metabolism in regulating ferroptosis, indicating potential combinational therapeutic strategies for cancer treatment. In this study, by drug combination screen of lipid metabolism compounds with ferroptosis inducers in decreasing TNBC cell viability, we found potent synergy of the CB1 antagonist rimonabant with erastin/(1 S, 3 R)-RSL3 (RSL3) in inhibiting TNBC cell growth both in vitro and in vivo via promoting the levels of lipid peroxides, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and cytosolic reactive oxygen species (ROS) production, enhancing intracellular glutathione (GSH) depletion and inducing G1 cell cycle arrest. We identified that inhibition of CB1 promoted the effect of erastin/RSL3 on inducing ferroptosis and enhanced their inhibitory effect on tumor growth. Using RNA-Seq, fatty acid analyses and functional assays, we found that CB1 regulated stearoyl-CoA desaturase 1 (SCD1)- and fatty acyl desaturase 2 (FADS2)-dependent fatty acid metabolism via phosphatidylinositol 3 kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) signaling pathways to modulate ferroptosis sensitivity in TNBC cells. These data demonstrate that dual targeting of CB1 and ferroptosis could be a promising therapeutic strategy for TNBC.

Beneficial Effects of Theaflavins on Metabolic Syndrome: From Molecular Evidence to Gut Microbiome.

In recent years, many natural foods and herbs rich in phytochemicals have been proposed as health supplements for patients with metabolic syndrome (MetS). Theaflavins (TFs) are a polyphenol hydroxyl substance with the structure of diphenol ketone, and they have the potential to prevent and treat a wide range of MetS. However, the stability and bioavailability of TFs are poor. TFs have the marvelous ability to alleviate MetS through antiobesity and lipid-lowering (AMPK-FoxO3A-MnSOD, PPAR, AMPK, PI3K/Akt), hypoglycemic (IRS-1/Akt/GLUT4, Ca2+/CaMKK2-AMPK, SGLT1), and uric-acid-lowering (XO, GLUT9, OAT) effects, and the modulation of the gut microbiota (increasing beneficial gut microbiota such as Akkermansia and Prevotella). This paper summarizes and updates the bioavailability of TFs, and the available signaling pathways and molecular evidence on the functionalities of TFs against metabolic abnormalities in vitro and in vivo, representing a promising opportunity to prevent MetS in the future with the utilization of TFs.

Discovery of highly potent and selective CRBN-recruiting EGFRL858R/T790M degraders in vivo.

Currently, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC). However, the inevitable drug resistance and side effects are the current main obstacle, which motivating novel therapies. Proteolysis targeting chimera (PROTAC), a lately-developed technology to target proteins for degradation, has been utilized for drug development. Therefore, we designed, synthesized and evaluated a series of CRBN-recruiting EGFR degraders. Among them, 13a and 13b significantly inhibited NCI-H1975 cells proliferation with IC50 values of 58.08 nM and 46.82 nM, respectively, whereas exhibited more than 100 µM against A549 or H1299 cells, whose selectivity was more than 1700-fold. 13a and 13b potently induced the EGFRL858R/T790M degradation by ubiquitin proteasome system in a time- and dose-dependent manner but not that of EGFRWT, and the DC50 values of 13b was 13.2 nM, which was the most potent compound in current known CRBN-recruiting EGFRL858R/T790M degraders. 13a and 13b dramatically induced cell apoptosis, cell cycle arrest and inhibited downstream signaling pathways. Furthermore, 13a and 13b effectively and selectively inhibited NCI-H1975 xenograft tumor growth with good pharmacokinetics (PK) properties in vivo. These findings demonstrate that 13a and 13b could serve as candidates for developing the drug for treating NSCLC.

Design of Photosensitive Cobalt Complex Intermediates and Their Application in the Green Syntheses of Molecules Containing the Quinazolin-4(3H)-imine Scaffold.

Cobalt/photoredox cooperative catalysis is a well-explored technology for visible-light photoredox catalysis. Recently, the photosensitivity of Co(II) complexes in homogeneous catalysis has aroused the interest of scientists. In this study, photosensitive Co(II) complex intermediates were designed to develop new synthetic methods. These intermediates, consisting of Co(II) and two substrate molecules, bind to O2 and absorb visible light over a wide spectral range, triggering in situ oxidative decarboxylation to produce molecules containing the quinazolin-4(3H)-imine scaffold. These reactions employed glyoxylic acid and ketoacids as new building blocks, and good to excellent yields of the corresponding products were obtained under mild reaction conditions using green and inexpensive reagents and solvents. These results are of importance since the design of Co-based photosensitive intermediates will aid in establishing novel methods for harnessing visible light and hence lead to innovation in organic syntheses.

Pep5-based antitumor peptides containing multifunctional fragments with enhanced activity and synergistic effect.

In this study, we designed a series of hybrid peptides based on pep5-TAT (P-05), comprising antitumor segment (pep5), endosomal escape segment ((LLHH)3) and cell penetrating/membrane disrupting segment (TAT, R9, sC182). These peptides exhibited remarkable antitumor activity towards tumor cells (HepG2, A549). Among them, the IC50 values of peptide P-09 were 4.0 and 4.8 times lower than those of P-05 in HepG2 and A549 cells, respectively. It was proved that P-09 could enter tumor cells through endocytosis and direct penetration and induce the apoptosis and necrosis. The antitumor effects were attributed to the synergistic effect of membrane disruption and proteasome inhibition, which occurred during and after the cellular entry, respectively. The whole process was accompanied by excessive ROS production. In vivo, P-09 exhibited enhanced ability to inhibit the growth of HepG2 subcutaneous tumor xenografts than P-05 in nude mice. In brief, this work provided valuable insights into the design of peptide-based antitumor agents with synergistic antitumor effects.

Instant Dark Tea Alleviates Hyperlipidaemia in High-Fat Diet-Fed Rat: From Molecular Evidence to Redox Balance and Beyond.

Instant dark tea (IDT) is a new product gaining increasing attention because it is convenient and can endow significant health benefit to consumers, which is partially attributed to its high concentration of functional ingredients. However, the molecular mechanism underlying its regulatory effect on hyperlipidaemia is rarely studied. In this study, we performed omics and molecular verification in high-fat diet (HFD)-fed rat, aiming to reveal the mechanism and provide molecular evidence. The results showed that the major bioactive components in IDT were 237.9 mg/g total polysaccharides, 336.6 mg/g total polyphenols, and 46.9 mg/g EGCG. Rats fed with IDT (0.27-0.54 g/kg for 12 weeks) significantly reduced the body weight and TC, TG, LDL-C, blood glucose, and MDA and induced the level of serum HDL-C and also the levels of liver SOD, CAT, GSH-Px, and Nrf2, compared to HFD group. For molecular mechanism study, HIDT feeding had significant impact on the gene expressions of biomarkers in lipogenesis (FABP, CD36, SCD1, Cyp4a1, and Kcnn2), lipid oxidation (PPARγ), and glucose glycolysis (Gck and ENO2) in liver tissue. Moreover, gut microbiome study found that rats fed with IDT dramatically modified the gut microbial species at the family level, such as suppressing the increase abundance of Proteobacteria and Firmicutes induced by HFD. HIDT significantly boosted the relative composition of beneficial bacterium Akkermansia and Rikenellaceae_RC9_gut_group and decreased the relative abundance of the harmful bacterium Ruminococcaceae_UCG-005 and Ruminiclostridium_9, compared to HFD (p < 0.01). Correlation analysis between microbiome and animal indicators found that seven genera including Akkermansia, Clostridiales, Lachnospiraceae, Lachnospiraceae_UCG-010, Ruminiclostridium_9, Ruminococaceae-UCG-005, and Ruminocuccus_1 were found as potential biomarkers that were strongly correlated with oxidative stress and metabolism genes. For instance, Ruminococcaceae_UCG-005 was significantly correlated with body weight, TG, HDL-C, Nfr2, FABP3, SCD1, Cyp4a1, and Kcnn2. Collectively, the above data obtained in this study had provided the primary molecular evidence for the molecular mechanism and brought in novel insights based on omics for the regulatory effect of IDT on hyperlipidaemia.

Discovery of Novel Non-Oxime Reactivators Showing In Vivo Antidotal Efficiency for Sarin Poisoned Mice.

A family of novel efficient non-oxime compounds exhibited promising reactivation efficacy for VX and sarin inhibited human acetylcholinesterase was discovered. It was found that aromatic groups coupled to Mannich phenols and the introduction of imidazole to the ortho position of phenols would dramatically enhance reactivation efficiency. Moreover, the in vivo experiment was conducted, and the results demonstrated that Mannich phenol L10R1 (30 mg/kg, ip) could afford 100% 48 h survival for mice of 2*LD50 sarin exposure, which is promising for the development of non-oxime reactivators with central efficiency.

Discovery of highly potent and selective EGFRT790M/L858R TKIs against NSCLC based on molecular dynamic simulation.

Epidermal growth factor receptor (EGFR) is the most attractive target for drug research in non-small cell lung cancer (NSCLC). There have been three generation drugs developed to treat of NSCLC. The third-generation EGFR tyrosine kinase inhibitors (TKIs) Rociletinib and Osimertinib (AZD9291) achieved remarkable clinical efficacy. However, due to the inhibitory activity against the wild-type EGFR, the side effect of associated skin rash and gastrointestinal toxicity appeared. Thus, there is still an urgent need to develop novel inhibitors with potent inhibitory activity and high selectivity for T790M-containing EGFR over EGFRWT. Herein, guided by the molecular dynamic simulation results, a series of potent and selective Osimertinib derivatives were designed, synthesized and evaluated. The promising compounds 7f, 7g, 7k, 7m and 7n demonstrated excellent kinase inhibitory activity and high selectivity for EGFRT790M/L858R mutant. The selectivity of 7m to EGFRT790M/L858R was the highest in the current known compounds near to 2500-fold. In addition, the compound 7m showed considerable activity against NCI-H1975 and HCC827 cells, arrested NCI-H1975 cell cycle at the G2/M stage and significantly induced apoptosis in NCI-H1975 cell. These encouraged results indicated that 7m will be used as a candidate targeting EGFRT790M/L858R for further pharmacodynamic and pharmacokinetic studies, and all these studies provide important clues for the discovery of potent EGFRT790M/L858R inhibitors with high selectivity.

A novel chemical inhibitor suppresses breast cancer cell growth and metastasis through inhibiting HPIP oncoprotein.

Increasing evidence suggests the pivotal role of hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) in cancer development and progression, indicating that HPIP inhibition may be a promising target for cancer therapy. Here, we screened compounds inhibiting breast cancer cell proliferation with HPIP fused with green fluorescent protein as a reporter. A novel agent named TXX-1-10 derived from rimonabant, an antagonist of cannabinoid receptor 1 with anticancer effects, has been discovered to reduce HPIP expression and has greater inhibitory effects on breast cancer cell growth and metastasis in vitro and in vivo than rimonabant. TXX-1-10 regulates HPIP downstream targets, including several important kinases involved in cancer development and progression (e.g., AKT, ERK1/2, and FAK) as well as cell cycle-, apoptosis-, migration-, and epithelial-to-mesenchymal transition (EMT)-related genes. Consistent with the results of anticancer effects, genome-wide RNA sequencing indicated that TXX-1-10 has more significant effects on regulation of the expression of genes related to DNA replication, cell cycle, apoptosis, cell adhesion, cell migration, and invasion than rimonabant. In addition, TXX-1-10 significantly regulated genes associated with the cell growth and extracellular matrix organization, many of which were shown to be regulated by HPIP. Moreover, compared with rimonabant, TXX-1-10 greatly reduces blood-brain barrier penetrability to avoid adverse central depressive effects. These findings suggest that HPIP inhibition may be a useful strategy for cancer treatment and TXX-1-10 is a promising candidate drug for cancer therapy.