Zevaquenabant ((S)-MRI-1867) is a peripherally restricted, orally bioavailable dual CB1 receptor/iNOS inhibitor.Zevaquenabant ((S)-MRI-1867) (3 mg/kg, p.o.) ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury.The hybrid CB1R/iNOS inhibitor Zevaquenabant ((S)-MRI-1867) has greater antifibrotic efficacy than inhibition of CB1R alone.(S)-MRI-1867 reduced hepatic steatosis and the rate of hepatic VLDL secretion, upregulated hepatic LDLR expression, and reduced the circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) in diet-induced obesity (DIO mice).

Zebularine (NSC309132, 4-Deoxyuridine) is a nucleoside analog of cytidine and inhibitor of cytidine deaminase, also inhibits DNA methylation and tumor growth both in vitro and in vivo.

ZE132 is a potent and selective small-molecule inhibitor of PD-1/PD-L1 interaction with IC50 of <0.1 nM.ZE132 effectively inhibits the PD-1/PD-L1 interactions in vitro, and has a potent affinity to PD-L1.ZE132 shows robust anti-tumour effects in vivo, better than anti-PD-1 antibody.ZE132 treatment promotes cytotoxic T-cell tumour infiltration and induces IL-2 expression.ZE132 elicits strong inhibitory effects on the mRNA expression of TGF-β.

ZB-R-55 is a potent and selective RIPK1 inhibitor with IC50 of 5.7 nM, 10-fold more potent than GSK2982772.ZB-R-55 is a dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets.ZB-R-55 exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model.

YX-I-1 is a small-molecule modulator of human islet amyloid polypeptide (hIAPP) assembly, specifically inhibits amyloid formation; YX-I-1 inhibits the aggregation of wt hIAPP, extending the t50 from 15.1 ± 0.2 h to 23.4 ± 1.0 h at a 1:7 molar ratio of peptide:inhibitor. YX-I-1 inhibits primary nucleation, secondary nucleation and elongation of wt hIAP. YX-A-1 is a useful chemical tools to study hIAPP aggregation.

YX-A-1 is a small-molecule modulator of human islet amyloid polypeptide (hIAPP) assembly, specifically enhances amyloid formation; YX-A-1 accelerates wt hIAPP assembly, even when added in substoichiometric concentration ratios (e.g. at a peptide:YX-A-1 molar ratio of 1:0.5 the t50 is reduced ~1.5-fold). YX-A-1 is a useful chemical tools to study hIAPP aggregation.

YX-2-115 is a palbociclib derivative compound with piperazine-linker tail for PROTAC YX-2-107 synthesis, inhibits CDK6 with IC50 of 4.5 nM.

YTX-7739 is a potent, selective stearoyl-CoA desaturase (SCD) inhibitor with IC50 of 12 nM.YTX-7739 concentration-dependently reduces the fatty acid desaturation index (FADI), the ratio of monounsaturated to saturated fatty acids, with potential to treat synucleinopathies.

YTK-105 linker conjugate 1 is a PEG linker added to p62-ZZ ligand YTK-105 for AUTOTAC design.

YTK-105 is a small molecule p62-ZZ domain ligand, activate p62-dependent selective macroautophag, used for AUTOTAC design.

YQ-0629 is a specific HIF-2α inhibitor, binds to HIF-2α PAS-B domain with Kd of 57.5 uM.YQ-0629 could inhibit the expression of HIF-2α with or without the presence of PTX (3 nM) in MCF7 MS culture, does not bind to HIF-1α or affect the expression of HIF-1α.YQ-0629 suppresses self-renewal capacity and synergizes with PTX to reverse the chemoresistance of MCF7 MS.YQ-0629 inhibits growth of BCSCs derived from breast cancer patients and synergistically increases anti-BCSCs activity of PTX in vivo.

YOK-2204 linker conjugate 1 is a PEG linker added to p62-ZZ ligand YOK-2204 for AUTOTAC design.

YOK-2204 is a small molecule p62-ZZ domain ligand, activate p62-dependent selective macroautophag, used for AUTOTAC design.

YOK-1304 is a small molecule p62-ZZ domain ligand, activate p62-dependent selective macroautophag, used for AUTOTAC design.AUTOphagy-TArgeting Chimera (AUTOTAC) is a general chemical tool and platform technology, which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands.AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation.

YOK-1304 AUTOTAC intermidate 1 is an intermidate for AUTOTAC design.

YHV98-4 is a selective inhibitor of proton-selective ion channel Hv1 with IC50 of 0.7 uM; YHV98-4 displays no inhibitory effects against other channels containing VSDs, including hERG, KCNQ2, BK, and Nav1.7 channel. YHV98-4 did not inhibit transient receptor potential V1 (TRPV1) or A1 (TRPA1) at 20 uM, which also contains VSD-like domain. YHV98-4 restores impaired ROS-mediated inflammatory pathway, restores impaired ROS-SHP-1-PI3K/pAKT-CXCL1 pathway and attenuates morphine-induced hyperalgesia and tolerance.

YC8-02 is a small molecule mitochondrial-targeting SIRT3 inhibitor with IC50 of 0.53 uM.YC8-02 inhibits SIRT1 and SIRT2 with IC50 of 2.8 and 0.062 uM in in vitro biochemical assays.YC8-02 manifested increased ratio of mitochondria to total cell concentration, as measured by mass spectrometry in purified mitochondria extracts and total cell lysates.YC8-02 increased mitochondrial protein acetylation, inhibited GDH activity and induced autophagy in DLBCL cells.YC8-02 could phenocopy the effects of SIRT3 depletion.YC8-02 (30 mg/kg) caused regression of the tumors in DLBCL xenografts, with no evidence of discomfort or weight loss.

XY153 is a potent, BD2-selective BET inhibitor with IC50 of 0.79 nM for BRD4 BD2, 354-fold selectivity over BRD4 BD1.XY153 displays 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains.XY153 displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50=0.55 nM), also demonstrated good metabolic stability in vitro.

XP-524 (XL-223, XP524) is a potent, dual-BET/EP300 inhibitor, inhibits BRD4-BD (IC50=5.8 nM) and BRD4-BD2 (IC50=1.5 nM).XP-524 binds strongly to and inhibits EP300 and CBP proteins with IC50 of 28 and 116 nM, respectively.XP-524 (XL-223) showed high potency and selectivity (Kd < 1 nM) across BET family proteins. Selectivity for BRD proteins over all other bromodomain proteins was >400-fold.XP-524 significantly decreased expression of Myc pathway oncogenes such as c-MYC and n-MYC, increased expression of CDKN1B, a tumor suppressor that prevents the activation of the cyclin-D/CDK4 complex, and also reduced expression of cyclin-D (CCND1) itself.XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30.XP-524 prevented KRAS-induced, neoplastic transformation in vivo and extended survival in two transgenic mouse models of aggressive PDAC.

XMU-MP-5 is a new-generation potent and selective ALK inhibitor (IC50=4.15 nM) to overcome crizotinib resistance mutations, including L1196M and G1202R; XMU-MP-5 significantly induced apoptosis in EML4-ALK Ba/F3 cells did not affect apoptosis in wild-type Ba/F3 cells. XMU-MP-5 shows highest binding affinities for ALK and its mutants ALK(C1156Y) and ALK(L1196M), with K d values of 0.57, 0.4, and 0.77 nM, respectively. XMU-MP-5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild-type or mutant EML4-ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. XMU-MP-5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models.

XMU-MP-3 is a potent, selective, noncovalent BTK inhibitor with IC50 of 10.7 nM and 17.0 nM for BTK WT and BTK C481S mutation.XMU-MP-3 inhibited BTK‐transformed Ba/F3 cell proliferation with an IC50 of 11.4 nM, with negligible anti‐proliferative effects on parental wild‐type Ba/F3 cells (IC50>10 uM).XMU‐MP‐3 inhibited both the autophosphorylation and trans‐phosphorylation of BTK at residues Y223 and Y551, in a dose‐dependent manner in BTK‐transformed Ba/F3 cells at concentrations as low as 100 nM and completely suppressed at 1,000 nM.XMU‐MP‐3 was considerably less potent (IC50, 2,815 nM) against proliferation of BTK(T474M)‐transformed Ba/F3 cells.XMU‐MP‐3 inhibits the growth of malignant B‐cells, inhibited phosphorylation of PLCγ2 at Y1217 and Y759, substantially suppresses tumour growth in mouse xenograft models.XMU‐MP‐3 maintained inhibitory potency with an IC50 of 182.3 nM against BTK(C481S)‐Ba/F3 cells and with an IC50 of 17.0 nM in biochemical assays, suppressed ibrutinib‐resistant BTKC481S mutation in vivo.

XAF-1407 (XAF1407) is a novel putatively potent and highly specific IK,Ach (Kir3.1/3.4 and Kir3.4/3.4) inhibitor (IC50 of 1.1 and 3.2 nM, respectively).XAF-1407 displays highly selectivity other relevant cardiac ion channels, with selectivity ratios for Kir3.1/3.4 of >2,000–8,000 fold up to >27,000 fold for Nav1.5 and Kir2.1, respectively.XAF-1407 potently and selectively inhibited Kir 3.1/3.4 and Kir 3.4/3.4, underlying the IK,ACh current.XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly and successfully cardioverted atrial fibrillation (AF), although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration.

WW-III-55 is a high-affinity, selective dopamine D3 receptor (D3R) partial agonist with Ki value of 20 nM, exhibits >800-fold binding selectivity for D3R compared with the D2R.WW-III-55 (0-5.6 mg/kg) reduced cocaine self-administration, also reduced responding for sucrose and locomotor activity.WW-III-55 attenuated yawning induced by low doses of 7-OH-DPAT (a D3R-mediated behavior).WW-III-55 (10 mg/kg) inhibited the head twitch response (HTR) by 95% in DBA/2J mice.

WO95E is a novel potent, synthetic ligand (partial agonist) of PPARγ, directly binds to PPARγ with IC50 of 11 nM; WO95E's binding affinity is approximately 70-fold lower than that of UHC1 (Journal of Biological Chemistry. 2014;289(38):26618–26629.). WO95E significantly inhibited the S273 phosphorylation of PPARγ in 3T3-L1 differentiated adipocytes, led to the upregulation of the mRNA levels of a number of the PPARγ phosphorylation-dependent genes, including adiponectin, cycp2f2, Ddx-17, Rarres2, and Selenbp1. Unlike SR1664 and UHC1, WO95E does not bind to the canonical PPARγ ligand-binding pocket (LBP) containing H3, H3-4 loop, H11 and H12, which full agonist Rosi binds, instead, WO95E binds to the ABP comprising H2′-H3, β-sheet, and the Ω loop. WO95E improved glucose tolerance and insulin sensitivity in DIO mice.

WEHI-7326 (WEHI 7326) is a specifi mitotic inhibitor and potential anticancer agent, causes cell cycle arrest in G2/M, cell death in vitro (MDA-MB-231 IC50=24.4 nM), and displays efficacious anti-tumor activity in vivo.WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts.WEHI-7326 exceeded potency of myoseverin B by almost ten-fold, did not show any significant cytotoxic activity in vitro (IC50>40 uM) in HepG2 cells.WEHI-7326 prolongs survival in mouse models of high-risk neuroblastoma and leads to complete tumor regression when used in combination with standard-of-care relapse therapies.

Wee1 Inhibitor II is a potent, selective, ATP-binding site-targeting inhibitor of Wee1 with IC50 of 59 nM, 590-fold selectivity over the related checkpoint kinase Chk1 (IC50=35 uM).

WDR5 inhibitor 41 is a potent, selective and orally bioavailable WDR5 WIN-site inhibitor with TR-FRET Ki value of <0.02 nM, inhibits cell proliferation of MV4:11 and MOLM-13 with IC50 of 13 and 27 nM, respectively.WDR5 inhibitor 41 is well tolerated in mice by both iv and po dosing and showed no clinical sign of abnormalities suggesting an enhanced safetyprofile for the series.

Wbox2 is a membrane-permeant peptide that potently inhibits clathrin-mediated endocytosis (CME, IC50=3 uM), binds to SNX9 and AP2 and perturbs clathrin interactions with AP2 and SNX9.Wbox2 has no effect on cell viability at ≤30 uM and exhibited an IC50 for cytotoxicity (>40 uM) that is 10-fold higher than that needed to inhibit CME.Wbox2 interferes with AP2–clathrin interactions and alters CCP dynamics, binds to both AP2 and SNX9 with binding affinities of 4.0 and 26.2 uM.

VUBI1 is a potent activator of SOS1 which modulates the KRAS pathway, binds directly to SOS1 (Kd=44 nM); VUBI1 increase nucleotide exchange on RAS in vitro at sub-micromolar concentration, rapidly enhances cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2 (Hela pERK ICW EC50=5.9 uM).

VU6036720 (VU 6036720) is the first potent, selective inhibitor of heteromeric Kir4.1/Kir5.1 (KCNJ10/KCNJ16) with IC50 of 0.24 uM.VU6036720 displays >30-fold selective for Kir4.1/5.1 over homomeric Kir4.1 channels, Kir1.1, Kir2.1, Kir2.2, Kir2.3, Kir4.2, Kir6.2/SUR1, Kir6.1/SUR2b and Kir7.1.VU6036720 inhibits Kir4.1/5.1 activity through a reduction of channel open-state probability and single-channel current amplitude, does not induce diuresis in vivo.VU6036720 showwd an IC50 in 3 uM in Tl+ flux assays, approximately 7-times more potent at inhibiting Kir4.1/5.1 than fluoxetine and amitriptyline.VU6036720 represents the current state-of-the-art Kir4.1/5.1 inhibitor that should be useful for probing the functions of Kir4.1/5.1 in vitro and ex vivo.