Novel Potent Agonist of the Orphan G Protein-Coupled Receptor GPR17 (EC 50 27.9 nM)

ADAMTS-5-IN-3 (Example 37-2) is a potent inhibitor of ADAMTS-5 and ADAMTS-4 with IC50s of 8 and 12 nM, respectively. ADAMTS-5-IN-3 can be used for the research of diseases involving degradation of cartilage or disruption of cartilage homeostasis, in particular osteoarthrosis and/or rheumatoid arthritis.

MS9024 is the degrader for DNA methyltransferase 1 that degrades DNMT1 in cell HCT116 through the ubiquitin-proteasome pathway with a DC50 of 35 nM (DC50 in MDA-MB-468 and H1299 is 254 nM and 101 nM). MS9024 also inhibits DNMT1 with an IC50 of 0.43 μM.

C199 is a PROTAC degrader targeting PRMT4 (DC50 = 106 nM). C199 shows high selectivity for PRMT4 over other protein arginile methyltransferases. C199 exhibits strong cell degradation ability. C199 induces apoptosis in MM cell lines. C199 efficiently clears PRMT4 protein via the VHL-proteasome pathway. C199 has a relatively long half-life and shows strong anti-multiple myeloma (MM) tumor activity.

MMG-11 quarterhydrate is a potent and selective human TLR2 antagonist with low cytotoxicity. MMG-11 quarterhydrate inhibits both TLR2/1 and TLR2/6 signaling with IC50s of 1.7?μM for Pam3CSK4-induced hTLR2/1 and 5.7?μM for Pam2CSK4-induced hTLR2/6 responses.

MMG-11 is a potent and selective dual inhibitor of TLR2/1 and TLR2/6 signaling with low cytotoxicity.

ISM5939 is an orally active and selective ENPP1 inhibitor with an IC50 of 0.63 nM for 2,3-cGAMP degradation and 9.28 nM for ATP hydrolysis. ISM5939 has antitumor activity.

BioE-1197 is a novel Pask inhibitor. BioE-1197 is a compound that enhances T cell function. Functionally, treatment with BIOE-1197 significantly boosts the ability of effector T cells (such as CD8+, Th1, and Th2 cells) to produce lineage-specific cytokines upon restimulation. BIOE-1197 is considered a novel agent with potential applications in tumor immunotherapy and enhancing vaccine efficacy.

Emupertinib (example 37) is a potent EGFR inhibitor with IC50 values of <0.3 nM, 0.52 nM, 0.5 nM, 0.69 nM and 0.92 nM for EGFR (d746-750/T790M/C779S), EGFR (L858R/T790M/C797S), EGFR (d746-750/C797S), EGFR (L858R/C797S), and EGFR (wild-type), respectively.

KVS0001 is a specific and bioavailable small molecule inhibitor of SMG1 kinase, disrupts nonsense mediated decay (NMD).

STING inhbiitor, which inhibited the activation of the STING signal pathway and to prevent or treat a STING-​mediated disease.

RO5126766(CH5126766) is a Raf/MEK dual kinase inhibitor.

GSK898 is a potent, highly selective kynurenine monooxygenase (KMO) inhibitor with pIC50 of 8.8.

CT-996 is an orally active GLP-1RA agonist, with an EC50 of 0.49 nM. CT-996 reduces the β-arrestin recruitment and GLP-1R internalization. CT-996 suppresses postprandial blood glucose following a mixed meal tolerance test (MMTT) in mice expressing the human GLP-1 receptor and enhances glucose stimulated insulin secretion (GSIS) during an intravenous glucose challenge in obese monkeys. CT-996 can be used for the study of type 2 diabetes (T2D) and obesity.

Selumetinib (AZD6244) is selective, non-ATP-competitive oral MEK1/2 inhibitor, with an IC50 of 14 nM for MEK1. Selumetinib (AZD6244) inhibits ERK1/2 phosphorylation.

Mortaparib is a dual inhibitor of mortalin-PARP1 interaction, and a p53 activating cytotoxic compound, induces activation of growth arrest and apoptosis signaling in cancer cells in vitro and in vivo.

ZINC13000658 is a METTL inhibitor. ZINC13000658 exhibits significant anti proliferative activity in various cells and can induce G1 phase cell cycle arrest and apoptosis such as HepG2 (IC50 = 5.632 µM) and SNU-449 (IC50 = 6.184 µM) cells. ZINC13000658 may be related to the inhibition of the activity of multiple methyltransferases such as METTL1, 3, 6, 16, 18, etc. ZINC13000658 can be used for research on various types of cancer.

MKP10241 is an orally active GPR119 agonist. MKP10241 elevates cAMP levels in the GPR119 expressing cell line (EC50: 3.7 nM). MKP10241 reduces blood glucose levels and HbA1c in acute models and a chronic diabetic mouse model. MKP10241 also demonstrates excellent preclinical efficacy in acute as well as chronic rodent models of obesity, and MASH.

XL-3156 is a potent, selective, and cross-species cGAS inhibitor. XL-3156 can simultaneously occupy both allosteric and orthosteric sites, and inhibit the interaction and phase separation between cGAS and DNA by stabilizing the closed conformation of the activation loop. XL-3156 can be used in the research of autoimmune diseases, inflammatory conditions and other diseases.

Clozapine N-oxide is a major metabolite of Clozapine noted to decrease SR-2A (5-HT2 serotonin receptor) density in vitro.

SSCI-1 is a highly potent, selective NaV1.7 inhibitor with IC50 of 27 and 82 nM on human and rhesus Nav1.7 channels, respectively.SSCI-1 showed robust selectivity over other human and rhesus Nav channel paralogs, with the exception of Nav1.2 channels (IC50 252 nM for hNaV1.2), shows no other channels and receptors in 114 enzymatic, radioligand binding, and cellular assays.SSCI-1 also exhibits high potency in manual patch clamp experiments (IC50=66/295 nM for huma/rhesus Nav1.7 channels).SSCI-1 does not affect myelinated nerve excitability as measured by TT, SSCI-1 inhibits odorant-induced olfaction in the olfactory bulb of rhesus monkeys, measured by fMRI.SSCI-1 inhibits withdrawal responses to noxious heat in rhesus monkeys.

S217879 (S 217879) is a highly potent and selective NRF2 activator, binds to KEAP1 Kelch domain (SPR Kd=4.15 nM), disrupts the KEAP1-NRF2 interaction leading to robust NRF2 pathway activation.

Simepdekinra (Compound 221) is a IL-17A modulator with IC50s ≤10  nM and 10-100 nM for IL-17A/A HEK-Blue and IL-17A/F HEK-Blue cells. Simepdekinra can be used for inflammatory diseases such as psoriasis, ankylosing spondylitis and psoriatic arthritis research.

PA-915 (PA915) is a small-molecule, non-peptide antagonist of the PACAP type I (PAC1) receptor, inhibits PACAP (1 nM)-induced phosphorylation of CREB in PAC1/CHO cells with IC50 of <10 pM.

RPL11-MDM2 inhibitor S9 (J012-3168) is a small-molecule RPL11 mimetic and potential inhibitor of RPL11-MDM2 interaction, directly binds MDM2 and induces p53 stabilization and activation.

A derivative of the neurotransmitter GABA that acts as a GABAB receptor agonist.

GYS32661 is a potent, small-molecule inhibitor of RAC1 and its isoform RAC1B, specifically designed to target the Sonic Hedgehog (Shh) signaling pathway in cancers like medulloblastoma and colorectal carcinoma. Distinguishing itself from other RAC1 inhibitors, GYS32661 exhibits exceptional blood-brain barrier (BBB) permeability with an approximately 50% brain-to-plasma ratio, making it a premier candidate for treating CNS-related malignancies. It functions by disrupting the activation of RAC1 (IC50 ≈ 1.18 μM), subsequently reducing the expression of downstream transcription factors GLI1 and GLI2, which effectively halts tumor proliferation and metastasis. In preclinical in vivo models, the compound has demonstrated significant anti-tumor efficacy and a favorable safety profile without systemic toxicity. Due to its hydrophobic nature, it is typically formulated in a vehicle of DMSO, PEG300, and saline for administration. As a non-toxic clinical candidate, GYS32661 represents a promising therapeutic strategy for overcoming chemoresistance and improving survival rates in Shh-driven pediatric and adult tumors.

DF-003 is a selective, orally active, ATP-competitive, and brain-penetrant ALPK1 inhibitor. DF-003 potently inhibits human ALPK1 and ALPK1[T237M] with IC50s value of 1.5 nM and 16 nM. DF-003 exhibits more than 860-fold selectivity over the closest kinase. DF-003 inhibits TNF, CXCL10, or CXCL8 upregulation in HEK-293 cells. DF-003 can be used for the study of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) syndrome.

DF-006 is a small molecule, orally active Alpha-kinase 1 (ALPK1) agonist, activates ALPK1 and stimulates host innate immunity locally in liver, DF-006 enacts potent anti-HBV responses in mouse models of HBV and in primary human hepatocytes.

RSL3-NH2 is a GPX4 inhibitor and Ferroptosis inducer. RSL3-NH2 can be used as a cytotoxic payload for synthesis of antibody-drug conjugates (ADCs).