iHPCAL1 is a ferroptosis inhibitor that effectively inhibits RSL3-induced cell death, directly interacts with HPCAL1 and significantly inhibits HPCAL1 protein expression at 1.25-5 uM in HT-1080 and Calu-1 cells.iHPCAL1 delayed thermal-induced HPCAL1 protein degradation in cellular thermal shift assays (CETSAs), failed to affect the phosphorylation of PRKCQ, but inhibited the phosphorylation of HPCAL1 as well as the autophagic degradation of CDH2 induced by RSL3.The suppression of HPCAL1 phosphorylation and function induced by iHPCAL1 occurs downstream of PRKCQ phosphorylation.Bortezomib, but not chloroquine, prevented iHPCAL1-induced HPCAL1 protein degradation, iHPCAL1 stimulates the degradation of HPCAL1 through the proteasome pathway, thereby limiting ferroptosis.iHPCAL1 inhibited the anticancer activity of Imidazole ketone erastin (IKE) in a xenograft tumor model after inoculating HT-1080 cells into athymic nude mice or in an orthotopic pancreatic tumor model in which KPC cells, with no significant effect on IKE-induced GPX4 degradation in the xenograft tumor model.iHPCAL1 (10 mg/kg) protects against ferroptosis-associated acute pancreatitis in mice.

I-287 is a potent, selective, orally active inhibitor of PAR2, negative PAR2 allosteric modulator, inhibits PAR2-mediated activation of Gq and G12/13 but not Gi/o proteins (IC50=45-390 nM); I-287 is a negative allosteric modulator (NAM) and not an orthosteric competitive antagonist of hPAR2. I-287 inhibits PAR2-mediated activation of DAG/Ca2+/PKC and RhoA/SRF-RE, as well as FAK and ERK1/2 signaling pathways, shows no effect on PAR2-mediated recruitment of βarrestin2 and receptor internalization. I-287 inhibits PAR2-induced secretion of IL-8 cytokine in vitro and reduces Freund's adjuvant (CFA)-induced paw edema model in mice.

Hv1 inhibitor HIF is a novel inhibitor of the voltage-gated proton channel Hv1 interacts with the Hv1 VSD in the up and down states.HIF rapidly inhibits proton conduction in the up state by blocking the open channel.HIF interacts with a second site that is accessible in the down state and is responsible for key features of HIF-mediated inhibition, such as the slow component of current decay and the slow recovery from inhibition.The voltage-gated proton channel Hv1 plays important roles in numerous biological processes, including pH homeostasis, the immune response, and sperm cell function.Hv1 channel belongs to the large family of proteins containing voltage-sensing domains (VSDs), which also includes Nav, Kv, and Cav channels and voltage-sensitive phosphatases.

Human C53 peptide (C53, pGC-B activator C53) is a novel potent, selective particulate guanylyl cyclase B (pGC-B) activator, activates pGC-B/cGMP signaling pathway, and enhances cGMP generating actions.C53 is highly resistant to NEP degradation and has less interaction with NPRC compared to CNP in vitro.C53 activates the protective pGC-B/cGMP signaling pathway and possesses enhanced cGMP generating actions.C53 inhibits fibroblast proliferation chronically and suppresses the differentiation of fibroblasts to myofibroblasts.

HTH-02-006 is a potent, selective reversible inhibitor of NUAK1/2 with binding IC50 of 8/126 nM, respectively.HTH-02-006 reduces MYPT1(S445) phosphorylation in HuCCT-1 cells, suggesting NUAK1/2 inhibition.HTH-02-006 ameliorates YAP(S127A)-induced hepatomegaly, and reduces MYPT1(S445) phosphorylation.HTH-02-006 delays the outgrowth of YAP-induced HuCCT-1 xenograft tumors in nude mice.HTH-02-006 downregulated E2F, EMT, and MYC hallmark gene sets after NUAK2 inhibition in PC cells.HTH-02-006 slowed tumor growth and proliferation rates in a syngeneic allograft model and in radical prostatectomy patient derived explants.HTH-02-006 treatment led to inactivation of YAP and the downregulation of NUAK2 and MYC protein levels.

Hsp90α-IN-12h is the first Hsp90α-selective inhibitor with IC50 of 460 nM, exhibit 48-fold selectivity versus other Hsp90 isoforms.In NCI-H522 cells, Hsp90a-dependent substrates are readily degraded in the presence of Hsp90a-selective inhibitor.

Hsp90 inhibitor 5b is a first-in-class, small molecule inhibitor of the C-terminal (CTD) Hsp90 dimerization with KD of 3.42 uM, IC50 of 1.3 uM against leukemia cell line K562.Hsp90 inhibitor 5b inhibits Hsp90 chaperone function, does not show any interaction with the NTD of Hsp90.Hsp90 inhibitor 5b down-regulated the phospho-BCR-ABL1 and total-BCR-ABL1 levels, as well as the related downstream signaling pathways, additionally reduced the expression of client proteins associated with Hsp90 chaperone activity, involving Akt, Stat5, and c-Myc.Hsp90 inhibitor 5b inhibited leukemic cell lines (K562, KCL22 and HL60) proliferation and induced apoptosis in a caspase 3/7 enzyme-dependent assay.Hsp90 inhibitor 5b is effective against resistant leukemia cells and in the zebrafish xenotransplantation model.

HS-243 (HS243) is a highly potent, super-selective IRAK-1/4 inhibitor with IC50 of 24/20 nM, respectively.HS-243 shows exquisite potency toward IRAK-1/4 over all other human kinases with only minimal TAK1-inhibiting activity (IC50=0.5 uM).HS-243 binds in the ATP-binding pocket of IRAK-4.HS-243 potently reduces the proinflammatory response of RA cells and macrophages, has distinct cytokine profile from TAK1.HS-243 reduces percentage of survival in pancreatic and breast cancer cell lines.

HS-131 is an imaging probe of Hsp90 activity by linking it to a near-infrared (nIR) dye, HS131 uptake into cells correlated with cell membrane expression of Hsp90 and was used to image molecular subtypes of murine and human breast cancers in vitro and in murine models.

HPK1 inhibitor 1 is a highly potent, selective inhibitor of HPK1/MAP4K1 with biochemical IC50 of 0.0465 nM; displays >100-fold selectivity against 260 kinases in a panel of 265 kinases; HPK1 inhibitor 1 decreased SLP-76 phosphorylation in a human pSLP-76 ELISA at an IC50 lower than 0.02 uM; HPK1 inhibitor 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells; HPK1 inhibitor 1 demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production when combination with pembrolizumab in human PBMCs

HJ-01 is a small molecule that disrupts PTPσ-Trk interaction, enhances Trk signaling, and promotes sympathetic nerve regeneration over chondroitin sulfate proteoglycans (CSPGs).

HIV-1 Integrase inhibitor GS-B (GS-B) is a novel non-catalytic site integrase inhibitor of HIV-1 integrase (IN), inhibits the interaction between LEDGF IBD and IN with IC50 of 8.1 nM.GS-B displays antiviral potency in MT-4, MT-2, and human PBMCs with EC50 values of 18, 10, and 21 nM, respectively.

HIV-1 inhibitor 5b is a novel anti-HIV-1 compound that inhibits HIV-1 JR-CSF with EC50 of 1 nM without significant cytotoxicity (CC50>20 uM), also shows potency against NRTI- and NNRTI-resistant HIV-1 (EC50=1-3 nM); shows a chemical backbone similar to the clinically used integrase (IN) strand transfer inhibitor (INSTI) elvitegravir, but has no detectable INSTI activity; various drug-resistant HIV-1 strains did not display cross resistance to HIV-1 inhibitor 5b; remains its anti-HIV-1 activity even after the viral integration stage, significantly suppresses p24 antigen production in HIV-1 latently infected cells exposed with TNF-alpha; demonstrates favorable pharmacokinetic profiles in mice.

HIF inhibitor 208 is a small molecule inhibitor of HIF pathway with IC50 of 0.5 nM.

HHV protease inhibitor 43 is an irreversible small molecule inhibitor of human herpesvirus (HHV) protease targeting a non-catalytic cysteine (C161) with IC50 of 4 uM (HCMV), exhibits broad-spectrum inhibition of other HHV protease homologs.HHV protease inhibitor 43 demonstrates inhibitor stabilization of HCMV Pr homodimerization, exploiting a conformational equilibrium to block proteolysis.HHV protease inhibitor 43 causes a dose-dependent decrease in HCMV replication in HFF-1 cells with IC50 of 5 uM, with no significant cytotoxicity (CC50>20 uM).

HH-N25 is a a potent and selective topoisomerase I (TOP1) inhibitor with potent antiproliferative activities against a panel of human breast cancer cell lines (IC50=0.045-4.2 uM).HH-N25 shows potent antitumor activities in human breast cancer cells in vitro and in vivo.

HF50731 (HF-50731) is a novel potent, selective CXCR4 antagonist with Ki of 19.8 nM in the CXCR4 competitive binding assay.HF50731 significantly inhibited SDF-1α-induced calcium mobilization (IC50=621 nM) and cell migration, and blocked HIV-1 infection via antagonizing CXCR4 coreceptor function (IC50=1.5 uM).The structure-activity relationship analysis demonstrated that HF50731 could primarily occupy the minor subpocket of CXCR4 and partially bind in the major subpocket by interacting with residues W94, D97, D171, and E288.

HEI3090 (HEI-3090) is a small-molecule P2RX7 activator (positive modulator) of purinergic P2RX7 receptor (P2X7R), enhances the P2RX7-mediated intracellular calcium concentration (Emax=250 nM).HEI3090 inhibits tumor growth and combined with αPD-1 immunotherapy ameliorates mice survival.Dendritic cells (DCs) mediate the antitumor activity induced by HEI3090.HEI3090 induces the production of mature IL-18 in the presence of eATP, triggers antitumor responses mediated by IL-18-induced NK and CD4+ T cells.HEI3090 combined with αPD-1 induces antitumor memory immune response.

HDAC8 PROTAC 1 is a first-in-class proteolysis targeting chimera (PROTAC) for selective degradation of histone deacetylase 8 (HDAC8).HDAC8 PROTAC 1 induced degradation of HDAC8 without affecting the levels of other HDACs in cellular assays, and inhibited the growth of T-cell leukemia Jurkat cells more potently than a conventional HDAC8 inhibitor.

HCN4 inhibitor EC18 (EC18) is a HCN4-prefering blocker.

H210 is a potent dual Mdm2/MdmX inhibitor with Ki of 9.66/2.89 nM, respectively.

GW461484A (GW-461484A) is a potent small molecule capable of restoring caspofungin sensitivity, inhibits Yck2 kinase in C. albicans, originally discovered as an inhibitor of human p38α with IC50 of 150 nM.GW461484A inhibited a very narrow spectrum of human kinases. At 1 uM, it showed >80% binding to only 10 additional human kinases out of a panel of >400 kinases.Yck2 is the proximal target of GW responsible for restoration of echinocandin sensitivity in C. albicans, potently inhibits Yck2 kinase activity in vitro and impairs the virulence of C. albicans in co-cultures and in mice.GW461484A potentiates conventional antifungals against a broad range of pathogens.

GW440139B is a potent RIPK3 inhibitor, suppresses necroptosis driven by dimerizable RIPK3 with IC50 of 73.6 nM.GW440139B inhibits TNF- and TRIF-mediated necroptosis independent of RIPK1-RIPK3 interaction, directly inhibited RIPK3-mediated MLKL phosphorylation at Ser345, thus inhibiting necroptosis.

GSK812397 is a potent, selective, noncompetitive, orally available antagonist of CXCR4 receptor, inhibits entry of X4-tropic strains of HIV-1 with IC50 of 4.60 nM and 1.50 nM in PBMCs and HOS assays, respectively; does not block CCR5-mediated viral entry in the R5 viral HOS assay (IC50>25 uM); produces a concentration-dependent decrease in both an SDF-1-mediated chemotaxis and intracellular calcium release (IC50=0.34 nM and 2.41 nM, respectively) in cell-based functional assays; demonstrates antiviral activity against a broad range of X4-utilizing strains of HIV-1.

GSK737 (GSK-737) is a potent, highly selective BET BD2 inhibitor with pIC50 of 7.3 (BRD4 BD2), 200-fold selectivity over BRD4 BD1.

GSK693 (GSK-693) is a potent, direct inhibitor of M. tuberculosis enoyl-ACP reductase (InhA) with IC50 of 7 nM, shows equally potent activity against M. tuberculosis H37Rv both intra and extracellularly (MIC=0.2 uM); exhibits activities against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed.

GSK669 is a potent, selective NOD2 (nucleotide-binding oligomerization domain 2) inhibitor, inhibits muramyl dipeptide (MDP)-induced NOD2-mediated signaling (IC50=0.5 uM), has an IC50 of 3.2 uM for MDP-stimulated IL-8 secretion in HEK293/hNOD2 cells.GSK669 specifically inhibits MDP-induced NOD2 activation, has no effect on IL-8 secretion induced by over-expression of NOD1.GSK669 significantly inhibits platelet proinflammatory cytokine release induced by muramyl dipeptide, platelet aggregation, ATP release, and ROS generation induced by collagen and collagen related peptide (CRP). GSK669 inhibits thrombosis and oxidative stress via targeting platelet glycoprotein VI (GPVI), decreases malonaldehyde (MDA) and increases superoxide dismutase (SOD) levels in mouse plasma

GSK-588045 is a potent and selective 5-HT1A/B/D receptor antagonist with Ki of 9.5/8.8/9.8, respectively; exhibits high selectivity over human hERG potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models; demonstrates potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.

GSK-5498A is a potent, selective small molecule blocker of Calcium-Release Activated Calcium (CRAC) channel with IC50 of 1 uM; completely inhibits calcium influx through CRAC channels, inhibits mediator release from mast cells, and pro-inflammatory cytokine release from T-cells from multiple human and rat preparations.

GSK3β-IN-1a is a relatively selective and potent GSK-3β inhibitor with IC50 of 64 nM; induces replication of growth-arrested R7T1 β cells in a dose-dependent manner with EC50 of 1.1 uM, likely mediates β-cell proliferation through the Wnt signaling pathway.