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.

VU6028418 (VU 6028418) is a potent, highly selective, orally bioavailable M4 mAChR antagonist for the treatment of dystonia and other movement disorders.

VU6019650 is a potent, highly selective M5 mAChR orthosteric antagonist with IC50 of 36 nM, >100-fold selectivity against human M1-4.VU6019650 blocked the nonselective muscarinic agonist oxotremorine-M-induced increases in neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area.VU6019650 also inhibited oxycodone self-administration in male Sprague-Dawley rats without impair general motor output.

VU6015241 (VU 6015241) is a highly potent and selective antagonist of M4 muscarinic acetylcholine receptor (mAChR4) with IC50 of 71 nM.VU6015241 demonstrates selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.

VU6009048 is a potent, selective M4 positive allosteric modulator (PAM) with EC50 of 85 nM (hM4) and 379 nM (rM4).

VU6007215 is a potent, selective M4 positive allosteric modulator (PAM) with EC50 of 144 nM (hM4) and 295 nM (rM4).

VU0468554 (VU 0468554) is a nove potent, selective inhibitor of GIRK channel with IC50 of 0.85 and 2.6 uM for GIRK1/GIRK4 and GIRK1/GIRK2 in cellular assays.VU0468554 more effectively inhibits the cardiac GIRK channel than the neuronal GIRK channel, inhibits Gβγ-activated GIRK channels in noncompetitive and potentially uncompetitive fashion.VU0468554 competitively inhibits GIRK-channel activation by ML297, a GIRK-channel activator.In the isolated heart model, VU0468554 partially reversed carbachol-induced bradycardia in hearts from wild-type mice but not Girk4-/- mice.

VT02956 is a potent, specific inhibitor of Hippo pathway kinase LATS with IC50 of 0.76 nM (LATS1) and 0.52 nM (LATS2), respectively; VT02956 reduces YAP/TAZ phosphorylation in both dose- and time-dependent manner with IC50 of 0.16 μM and 0.43 μM in HEK293A cells and 4T1 cells, respectively. VT02956 suppresses ESR1 transcription, dramaticly reduces ERα and its target genes TFF1 and GREB1. VT02956 targets the LATS-YAP/TAZ-ERα axis to inhibit ER+ tumours cell growth, inhibits the proliferation of MCF-7 and T47D cells. VT02956 inhibits the growth of T47D cells with hormone therapy resistant ESR1 mutation (ERa Y537S or D538G), enhances the anti-tumour effect of palbociclib in ER+ breast cancer cells.

VT02484 is the negative control compound of VT02956, which is a highly potent Hippo pathway kinase LATS inhibitor.

VPC-13789 (VPC13789) is a potent, selective, orally available inhibitor of androgen receptor binding function-3 (BF3) site.VPC-13789 suppresses AR-mediated transcription, chromatin binding, and recruitment of coregulatory proteins.VPC-13789 selectively reduces the growth of both androgen-dependent and enzalutamide-resistant PCa cell lines.VPC-13789 demonstrated in vitro efficacy that reduced PSA production and tumor volume in animal models of CRPC with no observed toxicity.

Vornorexant (TS-142, ORN0829) is a potent dual orexin 1 and 2 receptor antagonist with IC50 of 1.05 and 1.27 nM for hOX1R and hOX2R, resepctively.Vornorexant (TS-142, ORN0829) exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study.Vornorexant (TS-142, ORN0829) is a viable candidate and is currently in clinical development for the treatment of insomnia.

VISTA inhibitor M351-056 is a small molecule compound having affinity with VISTA.

Vercirnon (GSK1605786A, CCX282-B) is a potent, selective, orally bioavailable antagonist of CCR9, inhibits CCR9-mediated Ca2+ mobilization and chemotaxis on Molt-4 cells with IC50 of 5.4 and 3.4 nM, respectively.Vercirnon (GSK1605786A, CCX282-B) displays high selectivity for CCR9 over CCR1-12 and CX3CR1-7 (IC50>10 uM).Vercirnon (GSK1605786A, CCX282-B) is an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC50 values of 2.8 and 2.6 nM, respectively.CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis.Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice.