protein interaction inhibition

Talabostat (PT100, Val-boroPro) is a potent, nonselective and orally available dipeptidyl peptidase IV (DPP-IV) inhibitor with a Ki of 0.18 nM. Talabostat is a nonselective DPP-IV inhibitor, inhibiting DPP8 9, FAP, DPP2 and some other DASH family enzymes essentially as potently as it inhibits DPP-IV[1]. Talabostat stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. The inhibition of two serine proteases, DPP8 and DPP9, activates the proprotein form of caspase-1 independent of the inflammasome adaptor ASC[2]. Talabostat competitively inhibits the dipeptidyl peptidase (DPP) activity of FAP and CD26 DPP-IV, and there is a high-affinity interaction with the catalytic site due to the formation of a complex between Ser630 624 and the boron of talabostat[3]. Talabostat can stimulate immune responses against tumors involving both the innate and adaptive branches of the immune system. In WEHI 164 fibrosarcoma and EL4 and A20 2J lymphoma models, PT-100 causes regression and rejection of tumors. The antitumor effect appears to involve tumor-specific CTL and protective immunological memory. Talabostat treatment of WEHI 164-inoculated mice increases mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells[3]. Talabostat treated mice show significant less fibrosis and FAP expression is reduced. Upon PT100 treatment, significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs are also observed. Treatment with PT100 in this murine model of pulmonary fibrosis has an anti-fibro-proliferative effect and increases macrophage activation[4]. [1]. Connolly BA, et al. Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potencyand in vivo efficacy and safety. J Med Chem. 2008 Oct 9;51(19):6005-13. [2]. Okondo MC, et al. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol. 2017 Jan;13(1):46-53. [3]. Adams S, et al. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004 Aug 1;64(15):5471-80. [4]. Egger C, et al. Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis. Eur J Pharmacol. 2017 Aug 15;809:64-72.

Dri-c21045 showed concentration-dependent inhibition of NF- B activation and all CD40L induced by B cell proliferation. IC50 was 17.1 M and 4.5 M, respectively.Dri-c21045 is an effective selective inhibitor of CD40-CD40L synergistic stimulator protein-pro

M-525 binds to menin (IC50: 3 nM) and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL regulated gene expression in MLL leukemia cells. M-525 is a first-in-class, highly potent, irreversible, and covalent menin-MLL

c-Myc inhibitor15 (Compound A5) is a selective c-Myc inhibitor that disrupts the interaction between c-Myc and Max, leading to c-Myc protein degradation and apoptosis (Apoptosis). It exhibits potent cytotoxic activity with IC50 values of 4.08 μM and 7.86 μM in A549 and NCI–H1299 lung cancer cell lines, respectively. In an allogeneic tumor model, c-Myc inhibitor15 demonstrated outstanding antitumor efficacy, achieving a tumor growth inhibition rate of 76.4% and significantly reducing c-Myc protein expression. This compound shows promise for research related to c-Myc-associated lung cancer.

Somatostatin RC 102 is a peptide hormone. It regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.

ZQ-16 is a potent and highly selective agonist for the G protein-coupled receptor GPR84, demonstrating a half-maximal effective concentration (EC50) of 0.213 μM, and it activates multiple downstream signaling pathways including calcium mobilization, inhibition of cAMP accumulation, phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2), receptor desensitization and internalization, and receptor-β-arrestin interaction, making it a useful tool compound for studying GPR84 function and a candidate for further optimization.

Sclerotiorin is a natural product isolated primarily from Penicillium species. It inhibits soybean lipoxygenase-1 with an IC50 value of 4.2 μM. Sclerotiorin also exhibits a number of other activities including inhibition of cholesterol ester transfer protein (IC50 = 19.4 μM),, inhibition of Grb2-Shc interaction (IC50 = 22 μM),, and antagonism of endothelin receptors (IC50 = 114 and 152 μM for human ETA and ETB, respectively).

Mivebresib (ABBV-075), also known as ABBV-075, is a potent BET inhibitor (bromodomain (BRD)-containing protein) with potential antineoplastic activity. Upon administration, the bromodomain inhibitor ABBV-075 binds to the acetyl-lysine binding site in the BRD of certain BRD-containing protein(s), thereby preventing the interaction between those proteins and acetylated histones. This disrupts chromatin remodeling, prevents the expression of certain growth-promoting genes, and leads to an inhibition of cell growth in susceptible tumors. Also a potent inhibitor of MYC and the TMPRSS2-ETS fusion proteins.

Claficapavir (A1752) is a potent nucleocapsid protein (NC) inhibitor that effectively binds the HIV-1 NC with a dissociation constant (Kd) of 20 nM, resulting in the inhibition of its chaperone properties. This specific molecular interaction leads to strong antiviral activity against HIV-1, with an IC50 of approximately 1 μM [1].

Azaphilone-9 (AZA-9) functions as an inhibitor of the HuR-ARE RNA interaction, with an inhibition constant (IC50) of 1.2 μM, by targeting the RNA-binding protein Hu antigen R (HuR). As HuR-RNA interactions play a critical role in stabilizing oncogenic mRNAs within tumors, Azaphilone-9 exhibits potential in inhibiting cancer cell growth and progression.

Menin-MLL Inhibitor 29 (Compound C1) is a Menin-MLL protein-protein interaction (PPI) inhibitor that demonstrates high affinity to Menin with a dissociation constant (K D) of 138 nM and impedes Menin's interaction with Menin-binding motif 1 (MBM1), as evidenced by an inhibition constant (IC 50) of 46 nM. Additionally, it exhibits anti-proliferative activity against HepG2 and Hep3B hepatoma cell lines with IC 50 values of 0.31 μM and 0.71 μM, respectively, and has been shown to inhibit tumor growth [1].

MK2-IN-5, a pseudosubstrate of Mk2 with an inhibition constant (K_i) of 8 μM, selectively targets the protein interaction domain of the MAPK pathway and inhibits the phosphorylation of HSP25 and HSP27 [1] [2] [3].

Cyclorasin 9A5 is a cell-permeable, 11-residue cyclic peptide that orthosterically disrupts the Ras-Raf protein interaction, demonstrating an inhibition concentration (IC50) of 120 nM [1].

Fli-1-IN-1 (compound 21) serves as a FLI1 inhibitor by binding directly to the EWS-FLI1 protein, disrupting its interaction with RNA helicase A. This inhibition holds potential anticancer properties [1].

CaMKI (299-320) is a peptide representing residues 299-320 of Calcium calmodulin-dependent protein kinase I (CaMKI). This segment, functioning as a protein kinase, exhibits a strong interaction with Ca 2+ -CAM (K d ≤1 nM), enabling it to phosphorylate specific substrate proteins and regulate their activity. It encompasses both the CAM-binding domain and the self-inhibition domain. CaMKI (299-320) is applicable for researching cellular physiological processes such as proliferation, differentiation, and apoptosis .