off-target

PTC299 ((4-chlorophenyl) (1S)-6-chloro-1-(4-methoxyphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate) is an orally active inhibitor of VEGFA mRNA translation and selectively inhibits VEGF protein synthesis at the post-transcriptional level. PTC299 is also a potent inhibitor of dihydrolactate dehydrogenase (DHODH).

TCMDC-135051 is a potent and selective PfCLK3 protein kinase inhibitor demonstrating significant antiparasiticidal activity (EC50=320 nM) while exhibiting minimal off-target toxicity. It effectively hinders the transition from trophozoite to schizont, impairs transcription, and diminishes transmission to the mosquito vector.

DL-Mannitol is a osmotic diuretic, it may play a role in reducing off-target 68Ga-PSMA renal uptake

BRD20322 is a novel potent inhibitor of spCas9 that disrupts spCas9-DNA binding and exerts dose and temporal control of spCas9 in human cell lines. It reduces off-target DNA editing events, enhancing the precision and safety of CRISPR-Cas9 gene editing.

ERK-IN-2, an ERK2 inhibitor, exhibits an IC50 value of 1.8 nM. At doses greater than 10 μM, it may induce off-target toxicity and/or activity [1].

GNE-4997 is a potent and selective inhibitor of the interleukin-2-inducible T-cell kinase (Ki: 0.09 nM). The correlation between the basicity of solubilizing elements in GNE-4997 and off-target antiproliferative effects reduces cytotoxicity.

Vc-MMAD, a drug-linker conjugate for Antibody-Drug Conjugates (ADCs), combines the ADC linker Val-Cit (Valine-Citrulline) with the potent tubulin inhibitor MMAD. This compound leverages the targeting capability of ADCs to deliver the cytotoxic agent MMAD specifically to cancer cells, enhancing therapeutic efficacy while minimizing off-target effects.

Antiviralagent 59 (compound 58) is a selective antiviral agent with drug-like properties, capable of inhibiting a broad spectrum of filoviruses. It demonstrates low off-target activity and inhibitory effects against replicative forms of Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV).

Antifibrotic agent 1 is an orally active medication designed to treat idiopathic pulmonary fibrosis (IPF). It effectively mitigates IPF-related processes, including TGF-β-induced epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transition (FMT), as well as profibrotic M2 polarization. Antifibrotic agent 1 selectively inhibits CSF-1R, PDGFR-α, and Src family kinases (SFKs), while sparing VEGFR, FGFR, and Abl to minimize off-target toxicity. In a bleomycin (BLM)-induced pulmonary fibrosis mouse model, it demonstrates strong antifibrotic activity.

Arg-IN-1 is a selective covalent inhibitor targeting Arginine (Arg), with IC50 values of 9.7 nM and 30.4 nM for FGFR2 and FGFR3, respectively. This compound is designed to potentially avoid the off-target toxicity of FGFR1/4 and overcome acquired resistance, offering potential in cancer therapies targeting FGFR.

Mitochondrial-IN (C458) is a potent inhibitor of mitochondrial complex I. It offers significant protection against Aβ toxicity, exhibits favorable pharmacokinetic properties, and has minimal off-target effects.

VU439 is a functionalized photoaffinity ligand of Elexacaftor. Maintaining the activity of Elexacaftor as a CFTR corrector, VU439 allows the identification of SCCPDH as a specific off-target protein of Elexacaftor via chemical proteomics.

MXC-017 is an apoptosis inducer capable of crossing the blood-brain barrier, specifically targeting glioma stem cells (GSCs). It effectively prevents the formation of radiation-induced GSCs while promoting G0/G1 cell cycle arrest and apoptosis. With minimal off-target effects, MXC-017 exhibits no significant cytotoxicity even at concentrations up to 10 µM. Additionally, it significantly extends the median survival in patient-derived orthotopic xenograft (PDOX) glioblastoma (GBM) mouse models when used in conjunction with radiation therapy.

CLM296 is a potent and selective inhibitor of ALDH1A3, with an IC50 of 2 nM. It does not exhibit off-target effects on the highly homologous ALDH1A1 isoform. CLM296 is capable of inhibiting ALDH1A3-driven breast cancer metastasis and can be utilized in the study of triple-negative breast cancer (TNBC).

PVTX-405 is a selective oral IKZF2 molecular glue degrader with a DC50 of 0.7 nM and a maximum degradation (Dmax) of 91%. It enhances degradation efficiency, significantly reduces off-target degradation, and minimizes hERG inhibition with an IC50 of 48 µM. PVTX-405 effectively inhibits MC38 tumor growth in Crbn391VC57BL/6 mouse xenograft models and shows superior synergistic anticancer effects when combined with immune checkpoint therapies (ICTs) such as anti-PD1 or anti-LAG3 antibodies.

HSV-1/HSV-2-IN-3 inhibits the helicase-primase complex of herpes simplex virus (HSV), interfering with the crucial processes of DNA unwinding and primer synthesis necessary for viral genome replication. In gD immunofluorescence assays containing 2% FBS, its EC50 against HSV-2 is 7.0 nM, while in assays with 10% human serum, the EC50 is 57.5 nM. Within qPCR replication analysis, the compound demonstrates an EC50 of 1.1 nM. Additionally, HSV-1/HSV-2-IN-3 exhibits strong selectivity against off-target interactions with human carbonic anhydrase (IC50 for hCA II ≈ 2.9 µM, and > 35 µM for hCA I). This compound is applicable in anti-HSV research.

AuristatinS is a potent anti-tumor agent that serves as an Auristatin payload. It effectively reduces the bystander effect and decreases off-target toxicity. In the Karpas/KarpasBVR cell model, AuristatinS exhibits excellent tolerability. It can be used as the cytotoxic component in antibody-drug conjugates (ADCs) for treating various types of cancer.

DENV-IN-13 (Compound 30) is an inhibitor of DENV2 protease with an EC50 of 9.8 μM in HeLa cells. It exhibits potent antiviral activity with minimal cytotoxicity and does not inhibit off-target enzymes such as thrombin and trypsin. DENV-IN-13 is applicable in flavivirus infection research.

Cs-2d is a selective inhibitor of the ceramide synthase Cer1. It exhibits potent inhibitory activity against Cer1 in C. neoformans, while maintaining low off-target effects on human hCerS1. Cs-2d demonstrates strong antifungal activity and significantly suppresses fungal growth. It is applicable in studies of invasive fungal infections.

H3R antagonist 6 (Compounds 3) (H3-2406) is a histamine receptor 3 (H3R) antagonist with an IC50 of 5.6 nM. The 18F-labeled version exhibits high radiochemical yield, molar activity, and moderate brain uptake, although it shows off-target binding with the Sigma-1 receptor. It serves as a radioligand for positron emission tomography (PET) imaging in the study of central nervous system (CNS) diseases.

Lu AE51090 is a highly selective agonist of the muscarinic M1 receptor, displaying minimal off-target activity across other muscarinic subtypes and a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, making Lu AE51090 a valuable pharmacological tool for studying muscarinic receptor function and selective receptor modulation.

(3S, 4S)-PF-06459988 is the less active S enantiomer of PF-06459988, a potent irreversible inhibitor of T790M mutant epidermal growth factor receptor (EGFR), exhibiting excellent selectivity against EGFR wild-type due to its minimally reactive electrophile, reducing off-target labeling likelihood.

UCSF678 is a 42 nM arrestin-biased partial agonist at the 5-HT5AR with a more restricted off-target profile and decreased assay liabilities compared to the commercial antagonist SB-699551. UCSF678 is a selective probe for studying the function of the 5-HT5AR [1].

UCSF686 is a UCSF678 analog that is devoid of the 5-HT5A potency, while preserving the off-target affinity (5-HT1A, 5-HT2B and 5-HT7). UCSF686 is recommended as a control compound when using UCSF678 for probing 5-HT5A-dependent activities in cultures and in vivo [1].