Cyclophilin

Cyclosporin C is a highly lipophilic cyclic peptide natural product, a member of the cyclosporin series of antifungal and immunosuppresive compounds - Cyclosporin A and B. The cyclosporins bind the cyclophilin intracellular proteins, highly conserved proteins involved in cis-trans isomerization of peptidyl-prolyl bonds and protein folding.

Cyclophilin inhibitor 1 is a potent and orally bioavailable cyclophilin A inhibitor, with a Kd of 5 nM, shows effective anti-HCV activity, with an EC50 of 98 nM for HCV 2a.

Alisporivir (DEB-025; Debio-025) is a cyclophilin inhibitor molecule with potent anti-hepatitis C virus (HCV) activity.

TMN355 is a potent chemical cyclophilin A inhibitor and reduces foam cell formation and cytokine secretion. TMN355 is used for atherosclerosis.

NIM811 ((Melle-4)cyclosporin; SDZ NIM811) is an orally bioavailable mitochondrial permeability transition and cyclophilin dual inhibitor, which exhibits potent in vitro activity against hepatitis C virus (HCV) .

RMC-5127 is an orally active, brain-penetrant, mutant-selective tri-complex inhibitor targeting RASG12V. It non-covalently binds to cyclophilin A (CypA), forming a binary complex that engages active RASG12V to create a high-affinity tri-complex, thereby sterically blocking RAS-effector interactions. RMC-5127 inhibits RAS signaling in KRASG12V-mutant cancer cells, suppressing proliferation and inducing apoptosis. It holds promise for the study of RAS-mutant cancers, including non-small cell lung cancer.

ERAS-0015 (Pan-RAS-IN-2) is a molecular glue that targets RAS by promoting the formation of ternary complexes with cyclophilin A (CYPA) and active RAS (ON) proteins. This interaction disrupts the binding of RAF to RAS, thereby inhibiting downstream signaling. Pan-rasin-2 exhibits significant antiproliferative activity in RAS-mutant cell lines and shows promise as an anti-tumor agent.

RMC-4998 is an orally active inhibitor that selectively targets the active, GTP-bound state of the KRAS^G12C mutant. It forms a ternary complex with intracellular cyclophilin A (CYPA) and activated KRAS^G12C, exhibiting an IC50 of 28 nM. RMC-4998 suppresses ERK signaling and induces apoptosis in KRAS^G12C-mutant cancer cells, making it a valuable candidate for tumor research.

RMC-7977 is an orally bioavailable, triple-complex RAS inhibitor that functions by simultaneously binding to cyclophilin A (CypA; K_d = 195 nM) and KRAS^G12V (K_d = 292 μM), facilitating the formation of a stable inhibitory complex. It exhibits broad-spectrum activity against RAS isoforms—including KRAS, NRAS, and HRAS—across both wild-type and mutant variants. RMC-7977 suppresses key oncogenic signaling pathways by inhibiting the phosphorylation of ERK, CRAF, and RSK, while promoting apoptosis through enhanced PARP cleavage. This dual mechanism results in significant tumor regression and reduced acquired resistance in KRAS^G12C-driven cancer models. It also shows favorable tolerability across a range of RAS-mutant tumor models, positioning it as a promising therapeutic candidate for RAS-driven malignancies.

Elironrasib is an orally active, covalent inhibitor specifically targeting the active GTP-bound form of KRAS^G12C (KRAS^G12C(ON)). It uniquely functions by forming a stable tri-complex with KRAS^G12C(ON) and cyclophilin A (CypA) within tumor cells, leading to steric hindrance that blocks the interaction between KRAS and its downstream effectors. This mechanism effectively suppresses RAS-mediated signaling, particularly the ERK pathway. Elironrasib induces apoptosis in KRAS^G12C-mutant H358 non-small cell lung cancer cells and demonstrates potent antiproliferative activity across KRAS^G12C-mutant cell lines, with a median IC₅₀ of 0.11 nM. Its high specificity and novel mechanism make it a promising therapeutic candidate for cancers driven by KRAS^G12C mutations.

HL001 is an oral small molecule inhibitor targeting Cyclophilin A (CypA) and acting as a receptor antagonist for Lysophosphatidic acid 1 (LPA1). This compound induces cell cycle arrest and apoptosis in tumor cells via p53 stabilization, achieved by down-regulating G3BP1 and promoting reactive oxygen species production and DNA damage. HL001 disrupts the MDM2-p53-72R interaction in a CypA-dependent manner, demonstrating significant antitumor activity. Additionally, HL001 serves as a valuable tool in the investigation of pulmonary fibrosis.

Ganoderic Acid D is a tetracyclic triterpenoid derived from Ganoderma lucidum, known for its role as an apoptosis inducer. This compound facilitates the upregulation of SIRT3 protein expression, leading to enhanced deacetylation of cyclophilin D (CypD). Ganoderic Acid D effectively disrupts energy metabolism in colon cancer cells by inhibiting glucose uptake, lactate production, and the synthesis of pyruvate and acetyl-CoA. Additionally, it demonstrates potent apoptotic effects in HeLa human cervical carcinoma cells, making it a valuable reagent for cancer research applications.

Rencofilstat (CRV431) is a potent pan-cyclophilin inhibitor that targets multiple cyclophilins with IC50 values of 2.5 nM for Cyp A, 3.1 nM for Cyp B, 2.8 nM for Cyp D, and 7.3 nM for Cyp G. This compound is effective in reducing fibrosis and tumor growth in chronic liver disease models. Rencofilstat is suitable for research applications related to nonalcoholic steatohepatitis (NASH), hepatocellular carcinoma, and liver diseases induced by viral hepatitis.

RM-046 is a selective inhibitor targeting the KRAS(Q61H) mutant, functioning through the formation of a ternary complex with cyclophilin A. This compound non-covalently binds to activated KRASQ61H, obstructing effector binding and thereby inhibiting downstream signal transduction pathways. RM-046 has demonstrated efficacy in suppressing ERK phosphorylation, stalling cancer cell proliferation, and promoting anti-tumor activity, including tumor regression in preclinical xenograft studies. It serves as a valuable tool for investigating KRASQ61H-associated malignancies.

RAS/RAS-RAF-IN-1 is a potent inhibitor targeting the RAS and RAS-RAF signaling pathways. With a dissociation constant (KD) in the range of 5.0 μM to 15 μM for cyclophilin A (CYPA), this compound demonstrates significant binding affinity. RAS/RAS-RAF-IN-1 exhibits notable antitumor activity, making it a valuable tool for cancer research and therapeutic development.

Brilliant Black BN is an azo dye with a notable application as an antiviral agent. It effectively inhibits the interaction between enterovirus 71 (EV71) and its uncoating factor, cyclophilin A, demonstrating significant potential in the treatment of viral infections. This compound serves as a valuable tool for research focused on antiviral mechanisms and infectious disease studies.

NIM258 is a potent nonimmunosuppressive cyclophilin inhibitor, specifically targeting cyclophilin A with a Kd of 1.2 nM. It exhibits significant anti-HCV activity, with an EC50 of 40 nM. This compound serves as a valuable tool for research into HCV infection and its associated pathways.

ASP5286 is a novel non-immunosuppressive inhibitor targeting cyclophilin, primarily designed for research applications related to Hepatitis C virus (HCV). This compound demonstrates potent antiviral activity, making it a valuable tool for investigating HCV replication and pathogenesis. Researchers can utilize ASP5286 in studies focused on the mechanisms of viral infection and the development of therapeutic strategies against HCV.

SMCypI C31 is a non-peptidic inhibitor of cyclophilin with significant peptidyl-prolyl cis/trans isomerase (PPIase) inhibitory activity, demonstrating an IC50 of 0.1 µM. This compound exhibits broad-spectrum antiviral efficacy against various HCV genotypes, including 1a, 1b, 2a, 3a, and 5a, with EC50 values ranging from 1.20 to 7.76 μM in subgenomic replicon assays. SMCypI C31 targets and disrupts the interaction between cyclophilin A and NS5A, making it a valuable tool for research into HCV therapies.

Cyclophilin Inhibitor 3 is a selective inhibitor of Cyclophilin A, demonstrating significant antiviral activity against Hepatitis C Virus (HCV) with an EC50 of 4.2 μM. This compound is essential for studies investigating the role of CypA in viral replication and may serve as a valuable tool for antiviral research and therapeutic development targeting HCV infections.

CypD-IN-5 is a selective inhibitor of cyclophilin D (CypD), a key regulator of mitochondrial permeability transition. This compound demonstrates significant potential in modulating mitochondrial function and may be particularly useful in studying neurodegenerative diseases such as Alzheimer's disease. Its application in research focuses on understanding the role of CypD in cellular stress responses and the underlying mechanisms of neurodegeneration.

Cyclosporin A-Derivative 1 (Free base) acts as a potent calcineurin inhibitor through its interaction with cyclophilin. This compound is derived from cyclosporin A and plays a critical role in immunosuppression by inhibiting T-lymphocyte activation. It is primarily utilized in research applications focused on transplant immunology and autoimmune disease modeling.

Cyclosporin A-Derivative 2 is a novel derivative of cyclosporin A known for its immunosuppressive properties. It exerts its effects by binding to cyclophilin, thereby inhibiting the activity of calcineurin. This compound is primarily utilized in research related to transplantation, autoimmune disorders, and T-cell activation. Its unique properties may facilitate studies aimed at understanding immune modulation and therapeutic interventions in related diseases.

CypD-IN-4 is a potent and selective inhibitor of cyclophilin D (CypD), exhibiting high affinity with an IC50 of 0.057 μM. This compound is valuable in researching various conditions related to oxidative stress, neurodegenerative diseases, liver dysfunction, aging processes, autophagy, and diabetes. CypD-IN-4 facilitates the exploration of CypD's role in these pathologies, providing insights into potential therapeutic strategies.

CypD-IN-3 is a potent and selective inhibitor of cyclophilin D (CypD), demonstrating high affinity with an IC50 value of 0.01 μM. This compound is valuable for studying a range of biological processes and diseases, including oxidative stress, neurodegenerative disorders, liver diseases, aging, autophagy, and diabetes. Its specificity towards CypD makes it an important tool for elucidating the role of this target in various cellular functions and pathological conditions.

CypE-IN-1 is a highly potent and selective inhibitor of cyclophilin E (CypE), exhibiting an IC50 of 0.013 μM and a Ki value of 0.072 μM. This compound is valuable for investigating the role of CypE in various pathological conditions, including oxidative stress, neurodegenerative diseases, liver disorders, aging processes, autophagy, and diabetes. Researchers can utilize CypE-IN-1 to explore therapeutic strategies targeting CypE-related pathways.

CypD-IN-29 is a selective inhibitor of Cyclophilin D (CypD), with a key dissociation constant (KD) of 88.2 nM. By targeting CypD, this compound interferes with its interaction with β-amyloid protein in mitochondrial environments, thereby mitigating the formation of mitochondrial permeability transition pores (mPTP). CypD-IN-29 is suited for research focused on Alzheimer's disease mechanisms and mitochondrial dysfunction in neuronal cells.

ZX-J-19j is a selective inhibitor of cyclophilin J, a crucial target involved in various cellular processes. This compound exhibits potent antitumor activity, making it a valuable tool for cancer research. Its ability to modulate cyclophilin J function provides insights into tumor biology and potential therapeutic pathways.

Cyclosporin A-Derivative 1 is a crystalline intermediate of cyclosporin A that functions primarily by inhibiting calcineurin through binding to cyclophilin. This compound exhibits significant immunosuppressive activity, making it valuable in research related to transplantation, autoimmune diseases, and T-cell signaling. Its utility in studying the mechanisms of immune modulation further enhances its relevance in pharmacological investigations.

RM-041 is a selective, orally active inhibitor targeting KRAS[G13C](ON), forming a covalent complex with both KRASG13C (ON) and Cyclophilin A. This compound effectively blocks the binding of RAS effector proteins through steric hindrance and irreversibly binds to Cys-13, leading to the inhibition of KRASG13C mutant cancer cell proliferation. RM-041 demonstrates significant regression of KRASG13C tumors in both cellular and xenograft tumor models and exhibits a synergistic effect in combination with upstream inhibitors, such as SHP2 inhibitors. It serves as a valuable research tool in studying non-small cell lung cancer.

KRASG12C IN-12 is a selective inhibitor of the KRASG12C mutant. This compound effectively forms a ternary complex with intracellular cyclophilin A (CYPA) and the activated KRASG12C, inhibiting its downstream signaling pathways. It has significant potential for research applications related to cancer biology, particularly in studies targeting KRAS-driven tumorigenesis.

Acetyl-cyclosporin A aldehyde is a derivative of Cyclosporin A featuring an acetyl group and a reducing aldehyde moiety. This compound serves as a molecular glue by effectively inhibiting calmodulin and binding to cyclophilin, which can influence the nuclear translocation of NF-AT and may lead to mitochondrial damage. Its unique properties make it valuable for research applications aimed at understanding calcium signaling pathways and mitochondrial dynamics in various biological contexts.

Talatisamine is an orally active cyclophilin D activator derived from the roots of Aconitum carmichaeli Debx. It functions primarily by preventing calcium-dependent opening of the mitochondrial permeability transition pore (mPTP) with an IC50 of 78 μM and inhibiting delayed rectifier K+ channels with an IC50 of 146 μM. Talatisamine demonstrates significant antioxidant and membrane-stabilizing properties, effectively inhibiting lipid peroxidation and preserving mitochondrial membrane integrity. Its diverse biological activities include antiarrhythmic, hypotensive, anti-inflammatory, anticancer, and neuroprotective effects, making it a valuable tool in the study of ischemic diseases, rheumatoid arthritis, inflammation-related conditions, and Alzheimer's disease.

RN-0001 is a potent inhibitor of cyclophilins, specifically demonstrating Ki values of 4.1 nM and 12.0 nM against Cyclophilin A (CypA) and Cyclophilin D (CypD), respectively. By directly binding to CypD, RN-0001 effectively inhibits its peptidyl-prolyl cis-trans isomerase activity, preventing mitochondrial permeability transition pore opening. This compound enhances mitochondrial function, diminishes reactive oxygen species (ROS) production, and downregulates lipogenic marker expression. Additionally, RN-0001 inhibits NF-κB p65 nuclear translocation and reduces the release of activated caspase-3 and cytochrome c, making it a valuable tool for investigating alcohol-associated liver disease.

Cymbimicin B is a secondary metabolite that specifically targets cyclophilin A, a member of the cyclophilin family of proteins. This compound exhibits impressive inhibitory activity, making it valuable for research into the role of cyclophilins in various biological processes, including immunosuppression and protein folding. Its unique mechanism of action positions Cymbimicin B as a useful tool in studies related to cellular stress responses and therapeutic applications in autoimmune diseases.

Cymbimicin A is a secondary metabolite that binds specifically to cyclophilin A. This interaction modulates various cellular processes, making it a valuable tool in studies related to immunology and cancer research. Its unique mechanism may provide insights into cyclophilin-mediated signaling pathways and potential therapeutic targets.