integrin in 2

Integrin-IN-2 is an orally bioavailable pan αv integrin inhibitor.Integrin-IN-2 can increases the αvβ6, αvβ3, αvβ5 and αvβ8 binding affinities with pIC50 values of 7.8, 8.4, 8.4 and 7.4, respectively.

αvβ1 integrin-IN-1 TFA is an effective and selective αvβ1 integrin inhibitor (IC50: 0.63 nM).

αvβ1 integrin-IN-2 (compound 32) is a potent inhibitor of ανβ1 and α5β1 integrins, exhibiting IC50 values of 0.9 nM and 33 nM, respectively. This compound also inhibits other integrins with IC50 values of 380 nM (ανβ3), 280 nM (ανβ5), 230 nM (ανβ6), and 87 nM (ανβ8), as determined by the SPRA assay [1].

αvβ5 integrin-IN-2 (Cpd_AV2) is an inhibitor that targets the β-propeller central pocket of ITGAV (integrin αV) and disrupts the stability of integrin heterodimers. This compound induces cellular apoptosis [1].

1. Chelidonine (Stylophorin) isolated from Chelidonium majus efficiently induced apoptosis in HeLa cells through possible alteration of p38-p53 and AKT PI3 kinase signalling pathways. 2. Chelidonine is a promising model compound for overcoming MDR and for enhancing cytotoxicity of chemotherapeutics, especially against leukaemia cells, its efficacy needs to be confirmed in animal models. 3. Chelidonine may be a potential therapeutic agent against metastasis of invasive human cancer cells, exhibits antimigratory and antiinvasive effects in MDA-MB-231 cells, by suppressing COL-induced integrin signaling, through inhibiting the formation of the IPP complex and subsequent downregulation of IPP downstream signaling molecules, such as Akt and ERK1 2.

1. Glaucocalyxin A (Leukamenin F)-SBE-β-CD could be useful with a better solubility and sustained function in drug delivery. 2. Glaucocalyxin A activates caspase-3, decreases BAD phosphorylation, and reduces the expression of X-linked inhibitor of apoptosis protein. 3. Glaucocalyxin A inhibits Akt phosphorylation, suppresses proliferation, and promotes apoptosis in a dose-dependent manner, but not in normal glial cells. 4. Glaucocalyxin A inhibits collagen-stimulated tyrosine phosphorylation of Syk, LAT, and phospholipase Cγ2, the signaling events in collagen receptor GPⅥ pathway. 5. Glaucocalyxin A could potentially be developed as an antiplatelet and antithrombotic agent, can inhibit platelet p-selectin secretion and integrin activation by convulxin, is a GPVI selective ligand.

GRGDSPK TFA (EMD 56574 TFA) is a peptide containing the Arg-Gly-Asp (RGD) sequence, serving as a competitive and reversible inhibitor of integrin-fibronectin binding. This compound is utilized in research to elucidate integrins' involvement in bone formation and resorption [1] [2].

BIO5192 hydrate is a selective and potent integrin α4β1 (VLA-4) inhibitor (Kd < 10 pM). The compound selectively binds to α4β1 (IC50 = 1.8 nM) over various other integrins and results in a 30-fold increase in mobilization of murine hematopoietic stem and progenitors (HSPCs) over basal levels[1][2].

Ac-MRGDH-NH2 is a pentapeptide containing the RGD sequence. It is utilized in the synthesis of the diastereomeric prodrugs Λ- and Δ-[Ru(Ph2phen)2(κS,κN-(Ac-MRGDH-NH2))]Cl2. In these prodrugs, Ac-MRGDH-NH2 serves as a photolabile protecting group for the cytotoxic diruthenium aqua complexes [Ru(Ph2phen)2(OH2)2]2+, offering integrin targeting and photoactivation properties. Consequently, Ac-MRGDH-NH2 can be applied in studies exploring tumor-targeted photoactivatable chemotherapy.

QLT0267 is an inhibitor targeting integrin-linked kinase (ILK; IC50= 26 nM), showing over 10-fold selectivity against cyclin-dependent kinases 1, 2, and 5 (Cdk1, Cdk2, and Cdk5), and over 1,000-fold selectivity against C-terminal Src kinase (CSK), DNA-PK, Pim-1, Akt, PKC, and casein kinase 2 (CK2) at a concentration of 10 mg/ml. This compound effectively inhibits the proliferation of NPA187 papillary thyroid cancer cells with an IC50 of approximately 3 µM and induces apoptosis in NPA187, DRO, and K4 cancer cell lines. In vivo studies reveal that QLT0267, administered at 100 mg/kg, significantly reduces tumor growth in a DRO mouse xenograft model and diminishes both tumor volume and intratumoral vascularization in a U87MG glioblastoma mouse xenograft model, showcasing its potential for therapeutic applications in cancer treatment.

RGD peptide (GRGDNP) TFA functions as an inhibitor of integrin-ligand interactions, competitively blocking α5β1's interaction with the extracellular matrix (ECM). It induces apoptosis by triggering conformational changes that facilitate pro-caspase-3 activation and autoprocessing. Furthermore, RGD peptide (GRGDNP) TFA is critical in regulating cell adhesion, migration, growth, and differentiation [1] [2] [3].

Cilengitide is a potent integrin inhibitor for αvβ3 receptor and αvβ5 receptor with IC50 of 4.1 nM and 79 nM in cell-free assays, respectively; ~10-fold selectivity against gpIIbIIIa. Phase 2.

Compound 11, an α4 integrin receptor antagonist, exhibits oral activity and functions as an antagonist of the α4 integrin receptor. It efficiently inhibits the adhesion of K562 cells mediated by the interactions of α4β1 VCAM-1 and α4β7 MAdCAM-1, with IC50 values of 130 nM and 2 nM, respectively. Compound 11 also shows potential for use in studies using the DSS (dextran sulfate sodium) induced colitis mouse model.

αvβ6-IN-2 (compound 20) is an effective orally active inhibitor of αvβ6 integrin (αvβ6integrin), with a pIC50 value of 7.8. It shows potential for use in research on idiopathic pulmonary fibrosis.

RGD-4C, an arginine-glycine-aspartic acid peptide (ACDCRGDCFC), exhibits integrin binding activity. The primary integrin recognition site in extracellular matrix proteins, the Arg-Gly-Asp (RGD) sequence, allows peptides with this sequence to mimic matrix proteins' recognition specificity. As an αv-integrin ligand, RGD-4C can be conjugated with bioactive molecules to demonstrate antitumor effects in animal models [1] [2] [3].

ILK-IN-2 (OSU-T315) is a novel potent, orally active ILK (integrin-linked kinase) inhibitor with IC50 of 0.6 μM.

Echistatin TFA, the smallest active RGD protein from snake venoms, is a potent inhibitor of platelet aggregation, bone resorption in culture, and an antagonist of αIIbβ3, αvβ3, and α5β1[1][2][3][4].

Integrin modulator 1 is a potent and selective α4β1 integrin agonist, with an IC50 of 9.8 nM for RGD-binding α4β1, and increases cell adhesion mediated by α4β1 integrin, with an EC50 of 12.9 nM[1].

2-Methylbutyrylcarnitine (chloride) acts as a gut microbial metabolite that targets integrin α2β1 on platelets, facilitating the activation of cytosolic phospholipase A2 (cPLA2) and enhancing platelet hyperresponsiveness. This compound further augments platelet hyperreactivity and promotes thrombus formation in mice. It is also characterized as a branched-chain acylcarnitine.

KIN-8194 is a dual inhibitor of HCK and BTK, effective when administered orally, displaying IC 50 values of 0.915 nM for HCK and <0.495 nM for BTK. It inhibits growth and disrupts integrin-mediated adhesion in BTKi-resistant mantle cell lymphoma (MCL). Additionally, KIN-8194 has shown efficacy in overcoming ibrutinib resistance, enhancing survival in TMD-8 ABC DLBCL xenografted mice [1] [2].

Nexinhib20 is an inhibitor of exosome synthesis and transport with anti-inflammatory activity, inhibits RAB27A and neutral sphingomyelinase 2 (nSMase2) nsMase2, inhibits IL-8-induced β(2) integrin-dependent adhesion of human neutrophils in the subfluidic phase, and inhibits neutrophil adhesion and β(2) integrin activation through antagonism of the rac-1-guanosine 5'-triphosphate interaction. beta(2) integrin activation.