NAV-2729 / Navigen, University of Utah - LARVOL DELTA

Mechanisms of extracellular vesicle uptake in chemotherapy resistant and sensitive ovarian cancer: insights into tropism and resistance transfer (AACR 2025) - "All EVs were tested for uptake in both cisplatin-sensitive and cisplatin-resistant cell lines to characterize their interactions comprehensively. In the serous subtype, ChemoRC-EVs exhibited higher tropism towards SKOV3 cis cells, with significant uptake also observed in SKOV3 wt cells. In SKOV3 wt cells, uptake inhibition by dynasore, nystatin, and NAV2729 revealed the predominant involvement of clathrin-mediated, caveolin-mediated, and receptor-mediated pathways. In SKOV3 cis cells, dynasore and NAV2729 confirmed clathrin- and caveolin-mediated endocytosis as the primary uptake mechanisms, with minimal receptor-mediated involvement."

Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Bcl2l12, a novel protein interacting with Arf6, triggers Schwann cell differentiation program. (PubMed, J Biochem) - "Specific inhibition of Arf6 and cytohesins by NAV-2729 and SecinH3, respectively, decreased expression of marker proteins 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and glial fibrillary acidic protein (GFAP)...The knockdown also led to decreased filamentous actin extents. These results suggest that Arf6 and Bcl2l12 can trigger Schwann cell differentiation, providing evidence for a molecular relay that underlies how Schwann cells differentiate."

IO biomarker • Journal • BCL2 • BCL2L12 • GFAP

Identifying the regulatory cascade governing amyloid precursor protein macropinocytosis and subsequent production of amyloid-beta. (AAIC 2024) - "The inhibition of Arf6 using NAV2729 prevented the recruitment of itself, Rac1, Cdc42, and RhoA at 30 sec... These results demonstrate the sequential recruitment of regulatory proteins which regulate macropinocytosis of APP in response to its crosslinking. Fe65 and Arf6 are rapidly recruited to APP, followed by sustained recruitment of Rac1, RhoA and Cdc42. These regulatory proteins could be targeted to modulate APP-lysosomal trafficking and reduce Aβ production."

Alzheimer's Disease • APP • CDC42 • RAC1 • RHOA

Structural and functional characterization of mycobacterial PhoH2 and identification of potential inhibitor of its enzymatic activity. (PubMed, Braz J Microbiol) - "In silico inhibitor screening revealed ML141 and NAV_2729 as two potential inhibitors of the catalytic activity of Mt-PhoH2. Mt-PhoH2 is essential for mycobacterial growth as its knockdown strain showed a decreased growth effect. Overall, the present article emphasizes the factors essential for the proper functioning of Mt-PhoH2 which is a participant in the toxin-antitoxin machinery and may also play an important role in phosphate starvation."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Adenosine diphosphate ribosylation factor 6 inhibition protects burn sepsis induced lung injury through preserving vascular integrity and suppressing ASC inflammasome transmission. (PubMed, Burns) - "ARF6 inhibition preserved vascular integrity by restoring expression of VE-cadherin and suppressed the spread of inflammation by affecting phagocytosis of ASC specks, thus protected against sepsis induced lung injury and improve survival of burn septic animals. The findings of this study implied potential therapeutics by which ARF6 inhibition can protect lung function from septic induced lung injury and improve outcomes in burn sepsis."

Journal • Acute Lung Injury • Anesthesia • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock • Thermal Injury • CDH5 • MPO

Addiction to Small Gtpase ARF6-Mediated Sphingolipid Homeostasis By AML but Not the Host (ASH 2023) - "Surprisingly, Tamoxifen-induced whole body KO of Arf6 in adult Arf6f/f; Rosa-CreERT2 mice led to healthy and grossly normal mice with a normal lifespan...Both NAV-2729 and A6-4471 inhibited AML cell line proliferation and reduced primary AML cell colony formation in lower μM range...Pharmacologically inhibiting ARF6 suppressed AML proliferation in vitro and in vivo in a genotype-agnostic fashion. Our study implicates ARF6 as a potentially actionable and safe target in AML."

Acute Myelogenous Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Psychiatry • CD34

Targeting Small GTPase ARF6 Suppresses AML and Spares Host's Normal Physiology (SOHO 2023) - "Surprisingly, Tamoxifen-induced whole-body knockout of Arf6 in adult Arf6f/f; RosaCreERT2 mice led to healthy and grossly normal mice with a normal lifespan...Pharmaceutical Targeting of ARF6: We and our collaborators have developed two generations of ARF6 small-molecule inhibitors, NAV-2729 and A6- 4471... High ARF6 expression correlates with worse survival of AML patients. Targeting ARF6 disrupts sphingolipid homeostasis in AML cells, suppresses their proliferation but spares the host's normal physiology."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3

Enterovirus 71 enters human brain microvascular endothelial cells through an ARF6-mediated endocytic pathway. (PubMed, J Med Virol) - "Murine experiments demonstrated that NAV-2729 significantly alleviated mortality caused by EV71 infection. Our study revealed a new pathway by which EV71 enters the HBMECs and provides new targets for drug development."

Journal • Infectious Disease

ARF6 is a host factor for SARS-CoV-2 infection in vitro. (PubMed, J Gen Virol) - "By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but on cholesterol...In addition, pharmacological inhibition of ARF6 with the small molecule NAV-2729 showed a dose-dependent reduction of viral infection...This highlighted a role for ARF6 in multiple cell contexts. Together, these experiments point to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2."

Journal • Preclinical • Hepatology • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

ANG1/TIE2 pathway inactivates ARF6 to stabilize retinal endothelial barrier function (ARVO 2023) - "In addition, endothelial-specific Git1 knockout mice were used to test dermal and retinal vascular permeability induced by VEGF combined with or without the treatment with ANG-1 or ARF6 inhibitor NAV-2729...Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Diabetic Retinopathy • Ophthalmology • Retinal Disorders • ANGPT1

The small molecule inhibitor NAV-2729 has a complex target profile including multiple ADP-ribosylation factor regulatory proteins. (PubMed, J Biol Chem) - "Finally, our screens identified 48 other possible targets of NAV-2729. These results illustrate the complexities of defining targets of small molecules and identify NAV-2729 as a model PH domain- binding inhibitor."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • ASAP1

Pharmacological Inhibition of Lipid Import and Transport Proteins in Ovarian Cancer. (PubMed, Cancers (Basel)) - "Overall, the small molecule inhibitors of lipid handling proteins BMS309403, HTS01037, NAV2729, SB-FI-26, and sulfosuccinimidyl oleate (SSO) caused a drug-specific, dose-/time-dependent inhibition of FA/LDL uptake, associated with reduced proliferation, cell cycle arrest, and apoptosis. Our findings indicate that OC cells are very sensitive to lipid deficiency. This dependency should be exploited for development of novel strategies against OC."

Journal • Dyslipidemia • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • ANXA5 • CASP3 • CD36

Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity. (PubMed, Pharmacol Res) - "Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis."

Journal • Osteoporosis • Rheumatology • ERN1 • XBP1

Computational and mutational hotspot analysis of mycobacterial inorganic pyrophosphatase and virtual screening of natural compounds to discover contemporary drug candidates: Trilateral approach that explores its GTPase activity. (PubMed, Biotechnol Appl Biochem) - "Virtual screening of 700 compounds from herbal ingredient targets (HITs) subset of zinc database showed ZINC000003979028, ZINC000003870413, ZINC000003870412, ZINC000150338758, ZINC0000070450948, ZINC000150338754, ZINC000095098891, ZINC000000119985 and ZINC000005085286 as the top target hits and Mac0182344 and NAV_2729 as the top GTPase inhibitor that would target and hinders Mt-PPa activity. Mt-PPa activity is temperature and pH sensitive as the mutation in the His 21 and His 86 residues shift the optimal pH. Virtual screening of 700 compounds from herbal ingredient targets (HITs) subset of zinc database showed ZINC000003979028, ZINC000003870413, ZINC000003870412, ZINC000150338758, ZINC0000070450948, ZINC000150338754, ZINC000095098891, ZINC000000119985 and ZINC000005085286 as the top target hits and Mac0182344 and NAV_2729 as the top GTPase inhibitor that would target and hinders Mt-PPa activity."

Journal • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Does coupling to ADP ribosylation factor 6 explain differences between muscarinic and other receptors in interaction with β-adrenoceptor-mediated smooth muscle relaxation? (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "in this issue demonstrates that NAV2729, an inhibitor of ADP ribosylation factor 6, inhibits contraction of isolated blood vessels elicited by muscarinic receptor agonists, but not by α-adrenoceptor agonists or KCl. Against this background, we discuss the role of ADP ribosylation factor 6 in cellular responses to G-protein-coupled receptor stimulation. While ADP ribosylation factor 6 apparently is the only promising molecular explanation for the relative resistance of smooth muscle contraction elicited by muscarinic agonists, the existing data are insufficient for a robust conclusion."

Journal • Review

Inhibition of neurogenic contractions in renal arteries and of cholinergic contractions in coronary arteries by the presumed inhibitor of ADP-ribosylation factor 6, NAV2729. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "The neurogenic and adrenergic character of EFS-induced contractions was confirmed by inhibition by tetrodotoxin and prazosin. In coronary arteries, NAV2729 (5 µM) inhibited concentration-dependent contractions induced by carbachol and methacholine...In both vessel types, NAV2729 does not inhibit contractions induced by receptor agonists other than those acting on muscarinic receptors. Addressing effects in other vessels and in other smooth muscle-rich organs merits further attention."

Journal • Cardiovascular • EDN1

A multifactorial assessment of the SRP pathway constituent FtsY as a vital mycobacterial constituent. (PubMed, Biotechnol Appl Biochem) - "After searching the inhibitor database, 14 GTPase and ATPase inhibitor Mac0182344, ML141, ITX3, NAV_2729, Br-GTP, Rhosin_HCl, Mac0182099, CCG_50014, CID_1067700, Mac0174809, Nsc_23766, Berberine, Nexinhib20 and EHT1864 were found to interact with FtsY. Further ML141 and NAV2729 found to decrease the enzymatic activity of FtsY as well as the mycobacterial growth. Therefore, the conclusive statement of the present manuscript can be stated as the FtsY plays major role mycobacterial cell survival and ML141 and NAV2729 can be used to constrain the SRP pathway."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

ADP ribosylation factor 6 promotes contraction and proliferation, suppresses apoptosis and is specifically inhibited by NAV2729 in prostate stromal cells. (PubMed, Mol Pharmacol) - "Significance Statement By knockout of ARF6 in prostate stromal cells, we demonstrate an involvement of ARF6 in promotion of prostate smooth muscle contraction and stromal growth, and define concentration ranges for their ARF6-specific inhibition by NAV2729. Besides the context of benign prostatic hyperplasia and lower urinary tract symptoms, analog ARF6 functions in contraction and growth appear possible in other smooth muscle-rich organs, which merits further attention considering the high clinical relevance of smooth muscle-based diseases."

Journal • Benign Prostatic Hyperplasia

[VIRTUAL] The monomeric GTPase ARF6 is required for smooth muscle contraction and stromal proliferation in the prostate, and is specifically inhibited by NAV2729 (EAU 2021) - No abstract available

[VIRTUAL] Neurogenic smooth muscle contractions of the male detrusor are suppressed by a mechanism which is sensitive to the ADP ribosylation factor 6 (ARF6) inhibitor NAV2729 (DGU 2020) - "The cholinergic agonist carbachol and the thromboxane A2 analog U46619 induced concentration-dependent contractions of detrusor tissues, which were not changed by NAV2729. NAV2729 selectively enhanced neurogenic, but not agonist-induced detrusor contractions, suggesting suppression of contractile neurotransmission in the detrusor by ARF6. Due to its opposing roles in the prostate (inhibition of contraction) and the bladder (promoting contraction), NAV2729 may represent an attractive compound to be tested for treatment of underactive bladder."