MC-100093 (MC100093) is a potent, orally bioavailable upregulator of GLT-1 and devoid of antimicrobial properties.MC-100093 enhanced uptake of glutamate into astrocytes in a mouse neuron/astrocyte co-culture model with IC50 of 0.1 uM.MC-100093 restored the expression of NA core GLT-1.MC-100093 (50 mg/kg) attenuated cue-primed relapse to cocaine-seeking without reducing motivation to consume regular chow or sucrose pellets or affecting body weight.

MB 07811 (MB07811) is an orally bioavailable, liver-targeted prodrug of MB07344, which is a thyroid hormone receptor-beta agonist (TRβ) agonist, efficiently converted to MB07344 by liver microsomes in vivo; reduces cholesterol and both serum and hepatic triglycerides at doses devoid of effects on body weight, glycemia, and the THA.

M4K2234 is a potent, selective ALK1 (ACVRL1) and ALK2 (ACVR1) protein kinase inhibitor with IC50 of 7 and 14 nM, respectively.M4K2234 inhibits only ALK1/2 and one additional off target (TNIK) by kinome-wide screening against 375 protein kinases at 1 uM.M4K2234 demonstrated in cell based target engagement assays with an IC50 of 83nM for ALK1 and 13 nM for ALK2.M4K2234 exhibits only very weak potency against ALK4/5.M4K2234 affects phosphorylation of SMAD1/5/8 that corresponds to BMP branch of signalling which is mediated, besides others, also by ALK1/2 kinases.M4K2234 has only a very weak effect on SMAD2/3 phosphorylation that corresponds to TGF beta branch of signalling which is mediated mostly via ALK4/5/7.

M4076 is a higly potent, selective, ATP-competitive inhibitor of ATM kinase with IC50 of 0.2 nM.M4076 sensitizes tumor cell lines to radiation therapy in vitro and strongly enhances the anti-tumor activity of ionizing radiation in vivo.

LY2775240 (LY-2775240) is a highly selective, potent and orally active inhibitor of phosphodiesterase 4 (PDE4) with IC50 of 0.09/0.09/2.4/0.14 nM for PDE4A/B/C/D.LY2775240 displays >200-fold selectivity over PDE10A, and >5000-fold selectivity over other PDE isoforms (IC50>10 uM).LY2775240 potently inhibits TNFα secreted induced by Toll‐like receptor 4 agonist LPS in a human whole blood assay, inhibited LPS‐stimulated TNFα but has no effect with the media‐only control.LY2775240 is more potent than apremilast (IC50, 18 nM vs. 290 nM), also affects E‐selectin, secreted IgG, plasminogen activator inhibitor‐1, and secreted IL‐10.

LSN3172176 is a novel potent, selectiive M1 mAChR partial agonist (EC50 2.4-7.0nM, Emax 43%-73%), shows binding selectivity for M1 mAChRs (Kd=1.5 nM); LSN3172176 is a potential PET tracer for assessment of M1 mAChR target engagement in the clinic and to further elucidate the function of M1 mAChRs in health and disease.

LSH-A54 is a potent, class I selective HDAC inhibitor with IC50 of 26.2 nM (HDAC1) and 59.3 nM (HDAC2); LSH-A54 displays no significant inhibition against HADC3/6 (IC50>10 uM). LSH-A54 exhibits antiproliferative properties against breast cancer cell lines T-47D (IC50=1.58 uM), MCF-7 (IC50=1.32 uM) and BT-474 (IC50=2.55 uM). LSH-A54 attenuates cell migration significantly in wound healing assay and comparably to the pan-HDACi vorinostat, whereas the HDAC1-3 selective HDACi entinostat has no significant effect on cell migration. LSH-A54 reduced the number of colonies significantly in clonogenic survival assay compared to entinostat and showed comparable activity to pan-HDACi vorinostat.

LS-106 is a novel, fourth‐generation EGFR inhibitor against C797S mutation, targeting both EGFR19del/T790M/C797S and EGFRL858/T790M/C797S with selectivity over EGFRwt.LS-106 potently and dose‐dependently inhibited the kinase activity of EGFR19del/T790M/C797S, EGFRL858R/T790M/C797S, EGFRL858R/T790M, and EGFR19del/T790M with IC50 values of 2.4 nM, 3.1 nM, 7.3 nM, and 74.1 nM, respectively.LS-106 exhibited much weaker effect against EGFRwt (IC50=151.5 nM) and EGFR19del (IC50=402.9 nM).LS‐106 not only strongly inhibited the EGFR‐C797S-mutant kinase but also inhibited some other kinases, such as RET, ACK1, and PDGFR‐β.LS‐106 not only inhibited the proliferation of BaF3‐EGFR19del/T790M cells (IC50= 0.09 uM) but also showed over 30‐fold stronger antigrowth activity than osimertinib in BaF3‐EGFR19del/T790M/C797S (IC50= 0.09 uM) and BaF3‐EGFRL858R/T790M/C797S (IC50= 0.12 uM) cells, respectively, elicits significant cell apoptosis in EGFR–triple‐mutant cells.Oral administration of LS‐106 (30 and 60 mg/kg) potently inhibited tumor progression in PC‐9‐OR NSCLC xenograft model with TGI of 83.5% and 136.6%, respecitvely.

LPXC-516 is a potent bacterial LpxC inhibitor with IC50 of 0.68 nM (P. aeruginosa LpxC), potent against the P. aeruginosa isolates with MIC90 of 2 ug/mL.

Lockdown is a selective, reversible and non-competitive inhibitor of the integrin phosphatase PPM1F (IC50=16.37 uM), blocks cancer cell invasion.Lockdown acts in a dose-dependent, allosteric manner with high selectivity for PPM1F.Lockdown does not inhibit other protein phosphatases (PTP1P, PTPRJ, PP5) in vitro and does not induce additional phenotypes in PPM1F knockout cells.Lockdown fully re-capitulated the phenotype of PPM1F-deficient cells, increased phosphorylation of PPM1F substrates and corruption of integrin-dependent cellular processes in Lockdown treated glioblastoma cells.Phosphatase PPM1F is a regulator of cell adhesion by fine-tuning integrin activity and actin cytoskeleton structures. Elevated expression of this enzyme in human tumors is associated with high invasiveness, enhanced metastasis, and poor prognosis.

Lockdown Ester Prodrug (Lockdown Pro) is the ester-modified Lockdown with increased membrane permeability and prodrug-like properties, a selective small-molecule inhibitor of the integrin phosphatase PPM1F, blocks cancer cell invasion.Lockdown Ester Prodrug (Lockdown Pro) effectively block PPM1F-mediated effects on integrin β1 and PAK in cells, Lockdown Pro suppresses tissue invasion by PPM1F-overexpressing human cancer cells.

LMP517 (NSC 781517) is a non-camptothecin, dual TOP1 and TOP2 topoisomerase inhibitor.LMP517 showed better antitumor activity than its parent compound LMP744 against H82 (small cell lung cancer) xenografts.

LM146 (LM-146) is a potent and selective inhibitor of pan-PB1 bromodomains (Polybromo-1 protein, PBRM1 or BAF180), binds to PB1(2), PB1(5), and SMARCA2B with KD values of 110, 61, and 2100 nM, respectively.LM146 displayed 34-fold selectivity profile for PB1(5) over SMARCA2, showed no binding to any bromodomains outside the sub-family VIII at 10 uM.PB1 (Polybromo-1 protein) is a component of the BRG1/BRM-associated factor (PBAF) complex, a human analog of the yeast switch/sucrose non-fermenting (SWI/SNF) complex. PB1 is a unique epigenetic reader that contains six distinct bromodomains, while other known bromodomain-containing proteins possess at most two bromodomains. The multi-subunit PBAF complex contains three bromodomain-containing proteins (BCPs): BRD7, a member of the sub-family IV, and SMARCA4 (also known as BRG1) and PB1, two members of the sub-family VIII.

LFF571 is a semisynthetic thiopeptide and bactericidal antibiotic that interferes with bacterial protein synthesis by inhibition of elongation factor EF-Tu, LFF571 is potent in vitro activity against C.difficile strains with MIC90 of 0.25 ug/mL.LFF571 demonstrated activity against most other Gram-positive rods and cocci (MIC50/90, 0.125/0.25 μg/mL) except for bifidobacteria and some species of lactobacilli, showed reduced active activity against Gram-negative anaerobes with MICs for Bacteroides fragilis of 4 and 8 μg/mL.LFF571 inhibits exogenous protein synthesis elongation factor EF-Tu and interferes with the ability for EF-Tu to deliver aminoacylated tRNA to the ribosome.

Leusin-1 (Leukemia specific inhibitor 1) is a cell cycle phase specific inhibitor that specifically arrest leukemia cells during G2-phase and triggers an apoptotic cell death (CCRF-CEM IC50= 2.66 uM and TOM1 IC50= 0.877 uM).Leusin-1 showed specificity towards acute lymphoblastic leukemia cells than other types of leukemias, non-bloodborne cancers, or normal cells.Leusin-1 also arrested cells with lower levels of p-H3 (present only in M-phase) and increased levels of Cyclin A (levels peak in G2-phase).Leusin-1 does not target tubulin, Leusin-1 inhibited colony formation similar to Taxol.

LDN192960 (LDN 192960) is a highly potent and selective DYRK2 inhibitor with IC50 of 13 nM toward DYRK2 at 50 uM ATP.LDN192960 suppresses Thr25 RPT3 phosphorylation in a dose-dependent manner in HEK293T cells transiently overexpressing DYRK2-FLAG, with maximal effects at 1-10 uM.LDN192960 does not inhibit any of the 130+ kinases including other CMGC kinase family members that are closely related to the DYRKs.LDN192960 binds to the ATP-binding pocket of DYRK2, also potently inhibits DYRK1A, DYRK3 and Pim with IC50 of <3, 122 and 10 nM, respectively.LDN192960 perturbs proteasome activity, induces cell death, and impedes proliferation and invasion on MDA-MB-468 cells.LDN192960 impedes MM progression and delays myeloma-mediated bone degeneration.LDN192960 induces cytotoxicity in bortezomib-resistant MM, both in cells and in vivo. significantly alleviates tumor burden in standard and PDX TNBC models.

LCC03 is a salicylanilide derivative and autophagy inducer, dose-dependently suppresses proliferation and retarded cell-cycle progression in CRPC cells (IC50, 0.69 to 4.8 uM).The classical autophagy features, including autophagosome formation and LC3-II conversion, were dramatically shown in LCC03-treated CRPC cells, which was associated with the suppressed AKT/mTOR signaling pathways, a major negative regulator of autophagy.LCC03 also showed an expanded morphology of the endoplasmic reticulum (ER), increased expression of the ER stress markers GRP78 and PERK, and eIF2α phosphorylation.The PERK-eIF2α pathway contributed to the LCC03-induced autophagy.LCC03 suppressed the growth of CRPC xenografts in mouse bone without systemic toxicity in tumor-bearing mice.

Lazucirnon (KST4290, ALK4290) is a small molecule, orally active inhibitor against CCR3, the natural receptor for chemokine eotaxin, decreases inflammatory cytokines in preclinical models.Lazucirnon (KST4290, ALK4290) blocks eotaxin from binding to its G-protein coupled receptor (GPCR) CCR3.CCR3 plays an important modulatory role in inflammation, immune cell recruitment, and neovascularization, processes important for the pathogenesis of wet age-related macular degeneration (wet AMD) and other neurological and immunological diseases.

LAS194046 (LAS-194046) is a potent, selective pan-JAK inhibitor with IC50 of 5.46/0.4/ 2.07 nM against JAK1/2/3, less potent in TYK2 activity (IC50=21.8 nM).LAS194046 is effective at blocking cytokine signaling depending on JAK1/JAK3, both in lymphocytes and monocytes, and JAK2/JAK2 in monocytes with IC50 of 16 nM, 26 nM and 37 nM, respectively.LAS194046 reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model.

Lapcin is a potent dual topoisomerase I/II inhibitor with nM to pM IC50s against diverse cancer cell lines (Colon cancer HT29 cell IC50=0.516 nM); Lapcin showed weak activity against DNA gyrase (IC50>20.5 uM). While only weakly active against DNA gyrase, lapcin was a potent of inhibitor of both DNA relaxation by topoisomerase I (IC50=2.17 uM) and DNA decatenation by topoisomerase II (IC50=7.53uM), 14 times more potent than the alkaloid camptothecin. Lapcin was more potent than the topoisomerase II inhibitor etoposide against all of the cell lines we tested, with the exception of the lung cancer cell NCI-H226, against which it was essentially equipotent. Cell lines expressing wild-type p53 (HCT116, H226, MCF7) tended to show higher IC50s than p53 reduced cell lines (NCI-H1299, HT29, Colo205, Hela).

KYT-36 is a potent, selective, and bioavailable inhibitor of P. gingivalis virulence factor gingipain K (Kgp, lysine-gingipain), potently and selectively inhibits Kgp with Ki of 0.27 nM, respectively.KYT-36 consists of benzyloxycarbonyl (BOC), L-glutaminyl (GLN), methylphenylamino (MPA), L-lysinyl (LYS), and benzylcarbamoyl (BCA) moieties.KYT-36 strongly inhibited degradation of host proteins in culture supernatants and abolished thriving of P. gingivalis in cell cultures and in periodontal pockets in vivo.KYT-36 prevented Kgp-triggered vascular permeability in guinea pigs, i.e. demonstrating its efficacy against bacterial virulence in vivo, with no toxicity effects.

KYT-1 is a potent, selective inhibitor of P. gingivalis virulence factor Arg-gingipain (Rgp) with Ki 40 nM (RgpA/B).KYT-1 showed significant inhibitory effects on SMC proliferation stimulated by Porphyromonas gingivalis.

KY19334 is a specific small molecule inhibitor of CXXC5-Dishevelled (Dvl) protein-protein interaction (PPI), restores the Wnt/β‐catenin signalling.KY19334 reverses obesity‐related metabolic diseases with adult tissue remodelling.Oral administration of KY19334 (25 mg/kg) suppressed fasting glucose levels improves obesity‐related insulin resistance with long‐lasting effect in HFD‐fed mice.KY19334 treatment improves hepatic glucose homeostasis. KY19334 enhances energy expenditure by increasing the thermogenic activity of beige‐fat tissues.KY19334 treatment restores β‐cell mass and functions in HFD‐fed and STZ‐induced diabetes mellitus (DM) mice.

Kv2.1-syntaxin inhibitor 15 (Kv2.1-syntaxin-IN-15, Cpd5) is a small molecule Kv2.1-syntaxin-binding inhibitor (IC50=5.5 uM) with neuroprotective properties.Kv2.1-syntaxin inhibitor 15 competitively binds syntaxin against C1aB-containing Kv2.1 peptides with IC50 of 5.5 uM.Kv2.1-syntaxin inhibitor 15 (10 uM) significantly diminished threo-β-benzyloxyaspartate (TBOA, 75 uM)-induced toxicity neuronal cultures, ameliorated significant cellular damage, by preventing the expression of enhanced Kv2.1-mediated K+ currents.Kv2.1-syntaxin inhibitor 15 is a first-in-class inhibitor of Kv2.1 binding to Syntaxin, likely due to inhibition of the C1a region of Kv2.1 binding to syntaxin.Cpd5 (10 μM) does not affect evoked AMPAR EPSCs in layer 2/3 corticocallosal neurons in the mouse auditory cortex.

KUSC-5037 (KUSC5037) is a novel effective HIF-1 inhibitor with IC50 of 1.2 uM against HIF-1 transcriptional activity.KUSC-5037 suppressed the HIF-1α (a regulatory subunit of HIF-1) mRNA, causing decreases in the gene expression of HIF-1 target genes such as carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) genes.KUSC-5037 directly targets ATP5B protein, a catalytic β subunit of mitochondrial FoF1-ATP synthase.

KUNB 31 is a potent, isoform-selective Hsp90β inhibitor with Kd of 0.18 uM, displays 50-fold selectivity over Hsp90α and Grp94; exhibits anti-proliferative activity against NCI H23, UC3, and HT-29 cancer cell lines with IC50 of 6.74 µM, 3.01 µM, and 3.72 µM, respectively; specificly induces the degradation of Hsp90β-dependent client proteins (EGFR, HER2, CDK4, CDK6, CXCR4 etc.) in cells.

K-tetracosapeptide (K-TC) is a peptide of 24 amino acids corresponding to the helix a5 in KRAS4B, potent inhibitor of KARATE (KRAS4B-RHOA-mTORC2 Ensemble), specifically targets the KRAS4B-RHOA interaction.

KRpep-2d (Ac-RRCPLYISYDPVCRR-NH2) is a potent, selective, cell-membrane permeable, cyclic peptide inhibitor of K-Ras(G12D) with IC50 of 1.6 nM, >10-fold selectivity over WT and G12C KRas; KRpep-2d significantly suppressed ERK-phosphorylation, downstream of K-Ras(G12D), along with A427 cancer cell proliferation at 30 μM peptide concentration.

K-Ras G12D inhibitor KS-58 is the first K-Ras(G12D) selective, bicyclic peptide inhibitor with binding Ki of 22 nM; KS-58 suppressed growth of A427 cells and PANC-1 cells (human pancreas carcinoma, G12D mutant) down to 21.1% and 50.1% at 30 uM. KS-58 showed significantly weaker cell growth suppression activities against A549 (human lung carcinoma, G12S mutant), H1975 (human lung carcinoma, WT), MIA PaCa-2 (human pancreas carcinoma, G12C mutant), and Capan-1 (human pancreas carcinoma, G12V mutant) cells. KS-58 reduced the phosphorylation of ERK down to 26.0% and 57.6% at 30 uM, respectively. Biotin-KS-58 exhibited stronger binding to K-Ras(G12D) than to other Ras proteins; KS-58 enters cells, binds to both forms of intracellular K-Ras(G12D)GDP/GTP, and inhibits K-Ras(G12D)GDP/GTP-effector protein interactions, thus preventing downstream Ras signal pathways, such as ERK, and suppressing cell proliferation. KS-58 exhibits anti-cancer activity when given as an intravenous injection to mice with subcutaneous or orthotropic PANC-1 cell xenografts.

KRAS G12C Pipetide (LVVVGACGVGK)