miransertib (MK-7075) / Merck (MSD), National Human Genome Research Institute - LARVOL DELTA

MK-7075 (Miransertib) in Proteus Syndrome (clinicaltrials.gov) - P2 | N=45 | Recruiting | Sponsor: National Human Genome Research Institute (NHGRI) | Trial completion date: Mar 2028 ➔ Jul 2028 | Trial primary completion date: Mar 2026 ➔ Jul 2026

Trial completion date • Trial primary completion date • AKT1

PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor ipatasertib in Rhabdomyosarcoma. (PubMed, Nat Commun) - "Here, we evaluate the activity of pan-AKT inhibitors Ipatasertib, ATP-competitive, and Miransertib, allosteric inhibitor, in RMS cell lines and fusion-positive/negative patient-derived xenografts (PDX). The antitumor activity of Ipatasertib is dose-dependent, reaching an effective intra-tumor concentration when administered at 25 mg/kg daily. This study unveils the role of PRKG1 in myogenesis and highlights the potential of PRKG1 as a clinical biomarker for Ipatasertib therapy in RMS."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

Craniofacial vascular malformation with PIK3CA activating mutation in a 15-year-old patient (ECP 2025) - "This mutation has been reported in vascular malformations and is druggable with AKT (miransertib) and PI3K (alpelisib) inhibitors. This case underscores the role of PIK3CA mutations in vascular malformations and their potential therapeutic relevance. Molecular profiling in vascular anomalies can guide therapeutic decisions, offering new treatment avenues for patients with refractory or symptomatic lesions. Further research is needed to establish standardized molecular-driven treatment strategies for these conditions."

Clinical • CALD • PDPN • PIK3CA

Safety findings from the phase 1/2 MOSAIC study of miransertib for patients with PIK3CA-related overgrowth spectrum or Proteus syndrome. (PubMed, Orphanet J Rare Dis) - P1/2 | "Miransertib was safe and tolerable in participants with a confirmed diagnosis of PROS or Proteus syndrome. Future investigations are needed to determine whether patients receive measurable clinical benefit from miransertib."

Journal • P1/2 data • Cardiovascular • Dental Disorders • Hematological Disorders • Stomatitis • Thrombosis • AKT1 • PIK3CA

A computational journey in anticancer drug discovery: Exploring AKT1 inhibition by novel oxadiazoles using molecular docking, ADMET, density functional theory and molecular dynamic simulation. (PubMed, Comput Biol Chem) - "Especially showing comparable stability to the reference molecule over 200 ns in MD simulations, the best top 2 hit compounds having binding affinity -10.7 kcal/mol for PCOS_ 133 (CID-164189) and -11.6 kcal/mol for PCOS3_42 (CID-158973) emerged as potential AKT1 inhibitors for cancer therapy in comparison to -11.6 kcal/mol and -14.7 kcal/mol binding affinity of Miransertib reference drug and IQO cocrystallized ligand of AKT1 protein PDB code 3O96. LEU-210, LEU-264, ASP-292, and TRP-80 are the important amino acid residues required for AKT1 inhibition. These results provide important new perspectives for the rational design and optimization of oxadiazole-based AKT1/PKB inhibitors, therefore laying a strong basis for experimental validation including further in-vitro and in vivo studies and PKB inhibitor development."

Journal • Oncology • AKT1

MK-7075 (Miransertib) in Proteus Syndrome (clinicaltrials.gov) - P2 | N=45 | Recruiting | Sponsor: National Human Genome Research Institute (NHGRI) | Trial primary completion date: Mar 2025 ➔ Mar 2026

Trial primary completion date • AKT1

A Study of the Safety and Tolerability in Participants With PIK3CA-related Overgrowth Spectrum or Proteus Syndrome Who Are Being Treated With Miransertib (MK-7075) in Other Studies (MK-7075-006) (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Sep 2026 ➔ Feb 2030 | Trial primary completion date: Sep 2026 ➔ Feb 2030

Trial completion date • Trial primary completion date

Enriched environment enhances angiogenesis in ischemic stroke through SDF-1/CXCR4/AKT/mTOR pathway. (PubMed, Cell Signal) - "AMD3100, ARQ092, and rapamycin inhibited SDF-1-induced cell migration. Collectively, these findings demonstrate that EE enhances angiogenesis and improves the IS outcomes through SDF-1/CXCR4/AKT/mTOR pathway."

Journal • Cardiovascular • Ischemic stroke • CXCL12 • CXCR4

GQ262 Attenuates Pathological Cardiac Remodeling by Downregulating the Akt/mTOR Signaling Pathway. (PubMed, Int J Mol Sci) - "Furthermore, GQ262 inhibited the Akt/mTOR signaling pathway activation induced by TAC or PE, with its therapeutic effects disappearing upon the addition of the Akt inhibitor ARQ092. These findings reveal that GQ262 inhibits cardiomyocyte hypertrophy and apoptosis through the Akt/mTOR signaling pathway, thereby reducing fibrosis levels and mitigating cardiac remodeling."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology

PRKG1 HINDERS MYOGENIC DIFFERENTIATION AND PREDICTS RESPONSE TO THE AKT INHIBITOR IPATASERTIB IN RHABDOMYOSARCOMA (SIOP 2024) - "Our aim was to evaluate the antitumor activity in RMS cell lines and patient-derived xenografts of two AKT inhibitors with different mechanisms of action: Ipatasertib, an ATP-competitive inhibitor, and Miransertib, an allosteric AKT inhibitor.Methods The cytotoxic effect of AKT inhibitors was evaluated in RMS cell lines and in fusion-positive (FP) and fusion-negative (FN) RMS patient-derived xenografts (PDX). High PRKG1 mRNA levels in PDXs and primary RMS tumors positively correlated with in vivo efficacy of Ipatasertib.Conclusions Conclusions : Ipatasertib effectively targets a subgroup of RMS, regardless of the fusion oncogene status, characterized by high PRKG1 expression. This study unveils the role of PRKG1 blocking myogenesis and highlights the potential of PRKG1 as a clinical biomarker for Ipatasertib therapy in RMS."

Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor

Hesperetin alleviates aflatoxin B1 induced liver toxicity in mice: Modulating lipid peroxidation and ferritin autophagy. (PubMed, Ecotoxicol Environ Saf) - "In AFB1-induced HepG2 cells, the addition of PI3K inhibitor (LY294002) and AKT inhibitor (Miransertib) confirmed that hesperetin regulated the PI3K/AKT/mTOR/ULK1 pathway to inhibit ferritin autophagy and reduced the degradation of ferritin in lysosomes. In summary, our results suggest that hesperetin not only regulates the antioxidant system but also inhibits AFB1-induced ferritin hyperautophagy, thereby reducing the accumulation of iron ions to mitigate lipid peroxidation. This work provides a fresh perspective on the mechanism behind hesperetin and AFB1-induced liver damage in mice."

Journal • Preclinical • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Oncology • CD80 • CXCL1 • GPX4

A conserved role for AKT in the replication of emerging flaviviruses in vertebrates and vectors. (PubMed, Virus Res) - "Here, we report the effect on ZIKV and USUV replication of two AKT inhibitors, Miransertib (ARQ-092, allosteric inhibitor) and Capivasertib (AZD5363, competitive inhibitor) in different mammalian and mosquito cell lines. However, the specific function of AKT may vary depending on the host species. A better understanding of virus-host interactions is therefore required to develop new treatments to prevent human disease and new approaches to control transmission by insect vectors."

Journal • Infectious Disease

Synergistic Effects of Neratinib in Combination With Palbociclib or Miransertib in Brain Cancer Cells. (PubMed, World J Oncol) - "Of the targeted agents, the irreversible pan-human epidermal growth factor receptor (HER) inhibitors neratinib and afatinib were more effective than erlotinib and lapatinib at inhibiting the growth of all HBCCLs, and the cyclin-dependent kinase (CDK)1/2/5/9 inhibitor dinaciclib was the most potent targeted agent. We found that treatment with Src/Abl/c-kit inhibitor dasatinib, signal transducer and activator of transcription (STAT3) inhibitor stattic, Abl/platelet-derived growth factor receptor (PDGFR)α/vascular endothelial growth factor (VEGFR)2/fibroblast growth factor receptor (FGFR)1 inhibitor ponatinib, and the tropomyosin receptor kinase (TRK)/ROS proto-oncogene 1 receptor tyrosine kinase (ROS)/anaplastic lymphoma kinase (ALK) inhibitor entrectinib, also inhibited the growth of all HBCCLs...In addition to inhibiting the proliferation of HBCCLs, treatment with neratinib, dinaciclib, dasatinib, stattic and trametinib inhibited the migration of brain tumor cell line..."

Combination therapy • Journal • Brain Cancer • Leukemia • Oncology • Solid Tumor • AKT1 • ALK • CDK1 • HER-2 • KDR • ROS1 • STAT3

Targeted therapy for capillary-venous malformations. (PubMed, Signal Transduct Target Ther) - "We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations."

Journal • Cardiovascular • Hematological Disorders • Pain • Pulmonary Embolism • Respiratory Diseases • PIK3CA

ED-71 Improves Bone Mass in Ovariectomized Rats by Inhibiting Osteoclastogenesis Through EphrinB2-EphB4-RANKL/OPG Axis. (PubMed, Drug Des Devel Ther) - "LY294002 (PI3K inhibitor) or ARQ092 (AKT inhibitor) was used to block PI3K/AKT pathway. ED-71 inhibits osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis, improving bone mass in ovariectomized rats. PI3K/AKT pathway is involved this process."

Journal • Preclinical • Osteoporosis • Rheumatology • EPHB4

The Combination of Afatinib With Dasatinib or Miransertib Results in Synergistic Growth Inhibition of Stomach Cancer Cells. (PubMed, World J Oncol) - "Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of patients with stomach cancer...Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor (TKI) lapatinib and the EGFR-specific TKI erlotinib in inhibiting the growth of HSCCLs. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs, with the IC50 values ranging from 2 nM to 7 µM...Treatment with neratinib, afatinib, dinaciclib, dasatinib, stattic, miransertib and paclitaxel significantly inhibited migration of stomach cancer cells...."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ALK • CD133 • CD44 • KIT • MET

CLINICAL IMPACT OF GENETIC TESTING IN VASCULAR ANOMALIES PATIENTS (ASPHO 2024) - "Our study demonstrates the clinical utility of using a precision medicine approach in patients with vascular anomalies, as this testing provided diagnostic clarity, identified actionable variants, and provided support for the use of targeted therapies."

Clinical • Oncology • ARID1A • BRAF • GNA11 • GNAQ • KRAS • MAP2K1 • NRAS • PIK3CA • PIK3R1 • PTEN • RASA1

Indication for a Pneumocystis Prophylaxis Therapy in Patients with Vascular Anomalies Treated with PIK3/AKT/mTOR Pathway Inhibitors: Experts' Opinion and Systematic Review from the Literature. (PubMed, Dermatology) - "Our study shows that even if PJP is a rare event, it may occur in patients with VAs treated with an mTOR inhibitor. Although our results cannot allow for revising guidelines, prophylaxis with TMP-SMX might be appropriate for a subgroup of patients with risk factors for PJP."

Review • Infectious Disease • Pneumonia • Respiratory Diseases

Kaposi's sarcoma-associated herpesvirus viral protein kinase augments cell survival. (PubMed, Cell Death Dis) - "Treatment of HUVEC-vPK cells with a pan-AKT inhibitor Miransertib (ARQ 092) reduced the overall phosphorylation of AKT, resulting in the cleavage of Caspase-3 and the induction of apoptosis. vPK expression also inhibited the cytotoxicity of cisplatin in vitro and in vivo. Collectively, our findings demonstrate that vPK's ability to augment cell survival and promote angiogenesis is critically dependent on AKT signaling, which is relevant for future therapies for treating KSHV-associated cancers."

Journal • Human Immunodeficiency Virus • Infectious Disease • Kaposi Sarcoma • Oncology • Sarcoma • Solid Tumor • AKT2 • CASP3 • PLEK

Alpelisib For PIK3CA-Related Vascular Anomaly (EADV 2023) - "Current and emerging targeted agents for PIK3CA-related disorders include sirolimus, miransertib and alpelisib. The study of vascular birthmarks is a rapidly evolving area of medicine as our knowledge of the genetic mechanisms underpinning these lesions advances. We present one of the first patients in Australia to be treated with alpelisib and highlight the importance of multidisciplinary care foregrounding the roles of dermatology, pathology, and genetics in the management of this case."

Dermatology • Dermatopathology • Endometriosis • Gynecology • Inflammation • Pain • Women's Health • PIK3CA

The Synergistic Effect of Zuogui Pill and Eldecalcitol on Improving Bone Mass and Osteogenesis in Type 2 Diabetic Osteoporosis. (PubMed, Medicina (Kaunas)) - "The PI3K inhibitor LY294002 or AKT inhibitor ARQ092 altered the synergistic action of both on osteogenic differentiation. The combined use of ZGP and ED-71 reduced blood glucose levels in diabetic mice and promoted osteogenic differentiation through the PI3K-AKT signaling pathway, resulting in improved bone mass. Our study suggests that the abovementioned combination constitutes an effective treatment for T2DOP."

Journal • Diabetes • Metabolic Disorders • Osteoporosis • Rheumatology • Type 2 Diabetes Mellitus

Molecular insights into the behavior of the allosteric and ATP-competitive inhibitors in interaction with AKT1 protein: A molecular dynamics study. (PubMed, Int J Biol Macromol) - "We studied the effects of four inhibitors, including MK-2206, Miransertib, Herbacetin, and Shogaol, on the inactive conformation of AKT1 protein and the effects of four inhibitors, Capivasertib, AT7867, Quercetin, and Oridonin molecules on the active conformation of AKT1 protein. As compared to other complexes in either of its two conformations, MK-2206 has a stronger binding free energy affinity in the inactive conformation, -203.446 kJ/mol. MM-PBSA calculations showed that the van der Waals interactions contribute more than the electrostatic interactions to the binding energy of inhibitors to AKT1 protein."

Journal • AKT1

Growth response and migration of brain cancer cell lines to treatment with agents targeting different members of the HER family, CDKs and other signalling pathways (AACR 2023) - "Of the HER inhibitors, neratinib and afatinib were more effective than erlotinib and lapatinib and inhibiting the growth of all HBCCLs at IC50 values below 700nM and 1.9 µM, respectively. Treatment with Src/Abl/c-kit inhibitor dasatinib, STAT3 inhibitor static, Abl/PDGFRα/VEGFR2/FGFR1 inhibitor Ponatinib and the TRK/ROS/ALK inhibitor entrecitinb also inhibited the growth of HBCCLs with IC50 value ranging from 0.06 - 2.96 µM, 1 - 3.8µM, 0.19- 0.42 μM and 2.85- 3.47μM, respectively...Finally, treatment with neratinib in combination with Palbociclib, AZD4547, trametinib and miransertib inhibited the growth of HBCCLs synergistically. Taken together, our results support further investigation on the therapeutic potential of irreversible pan HER in combination with the CDK inhibitor dinaciclib and other targeted agents in brain cancer."

Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CDK1 • CDK4 • ERBB3 • ERBB4 • HER-2 • MET • PDGFRA

Impact of treatment with agents targeting different members of HER family, CDKs and downstream cell signaling molecules on growth and migration of stomach cancer cells. (AACR 2023) - "Of these, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan has been approved for the treatment of patients with stomach cancer...Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual EGFR/HER2 TKI lapatinib and the EGFR specific TKI erlotinib in inhibiting the growth of HSCCLs...Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs and with the IC50 values ranging from 2nM to 7uM...Of the agent examined, neratinib, afatinib, dinacicilib, dasatinib, stattic and miransertib also inhibited the migration of stomach cancer cells. Finally, treatment with a combination of afatinib with dinaciclib, capmatinib, dasatinib, stattic, ponatinib or miransertib resulted in synergistic and..."

Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ALK • CD133 • CDK1 • KIT • MET

Low concentrations of tumor necrosis factor-alpha promote human periodontal ligament stem cells osteogenic differentiation by activation of autophagy via inhibition of AKT/mTOR pathway. (PubMed, Mol Biol Rep) - "Low concentrations of TNF-α promote hPDLSCs osteogenic differentiation by activation of autophagy via inhibition of AKT/mTOR signaling."

Journal • Dental Disorders • Oncology • Periodontitis • TNFA