MK-2206 / Merck (MSD) - LARVOL DELTA

AKT Signaling Regulates Agrin-Mediated Acetylcholine Receptor Surface Density. (PubMed, Medicina (Kaunas)) - "Materials and Differentiated C2C12 myotubes were stimulated with Agrin in the presence or absence of the AKT inhibitor MK2206 during either the formation or maintenance phase... these findings identify AKT as a regulator of Agrin-mediated AChR accumulation and maintenance in vitro. These findings identify AKT as a critical integrator of metabolic and synaptic signaling required for postsynaptic receptor stability, with implications for neuromuscular disorders and muscle atrophy."

Journal • CNS Disorders • Muscular Atrophy

A comprehensive approach to targeting PI3K and Hippo pathways in sarcomas (AACR 2026) - "Cells were treated with MK2206 (Akt inhibitor), Everolimus (mTORC1 inhibitor), Romidepsin (HDAC inhibitor) and VT-107 (TEAD inhibitor) alone or in combination. TEAD inhibition disrupts TAZ/YAP transcriptional activity downstream, while HDAC inhibition restores Hippo signaling and suppresses TAZ/YAP transcription, and PI3K pathway inhibitors reduce survival signaling. These findings provide rationale for further investigation into dual-pathway inhibition as a therapeutic strategy, including mechanistic studies and in vivo validation to define therapeutic windows and potential clinical applications."

Oncology • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Solid Tumor • LATS1 • MST1 • PTEN • TAFAZZIN

Impression of AKT inhibitor in chromatin accessibility in mCRPC (AACR 2026) - "The Androgen Receptor (AR) pathway is a primary target for metastatic castration-resistant prostate cancer (mCRPC) treatment, and AR blockade with enzalutamide is a well-established therapeutic option for targeting the AR pathway in mCRPC...In this study, LuCaP 167 patient-derived organoid (PDO) models were treated with AKT inhibitors (Ipatasertib and MK2206), and the chromatin landscape was studied using ATAC-seq...Interestingly, footprinting and motif analysis revealed several transcription factor motifs enriched by AKT inhibition, including KLF15, a tumor suppressor. While the results are preliminary, our data provide additional insights into AKT's influence on chromatin accessibility."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • KLF5

RAS mutations are involved in the formation of myeloid sarcoma via JAML-mediated PI3K/AKT activation (OeGHO-AHOP 2026) - "RAS mut are enriched in MS and drive its development through JAML-mediated PI3K/AKT activation, which can be therapeutically blocked by AKT inhibition."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Sarcoma • Solid Tumor • JAML • KRAS • NF1 • NRAS • PTPN11

STABILIZED MAFB ACTIVATES IGF-1/PI3K/AKT TO CAUSE FOCAL SEGMENTAL GLOMERULOSCLEROSIS IN MULTICENTRIC CARPOTARSAL OSTEOLOSIS: GENETIC AND PHARMACOLOGIC RESCUE (ISN-WCN 2026) - "Lowering MAFB dosage (MafbˆMCTO/−) is protective, and pathway inhibition—validated in cells (imatinib, MK-2206, linsitinib) and in mice (imatinib)—attenuates disease measures. The MAFB–IGF-1/PI3K/AKT axis therefore represents a tractable therapeutic target in MCTO-associated nephropathy."

Clinical • Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • CSF1R • IGF1 • IGF2 • IR • MAFB • NPHS1

SAV1 DEFICIENCY IN KIDNEY PROXIMAL TUBULES PROMOTES MALADAPTIVE REPAIR THROUGH THE AKT PATHWAY FOLLOWING ISCHEMIA-REPERFUSION INJURY (ISN-WCN 2026) - "The mice were then treated with MK-2206, an AKT inhibitor, or vehicle control...AKT activation was markedly increased in SAV1ptKO mice compared to WT mice 48 hours after IRI. Pharmacological inhibition of AKT improved kidney function and reduced tubular histological damage induced by IRI in SAV1ptKO mice.Conclusion These findings indicate that SAV1 deficiency in proximal tubules delays kidney restoration after IRI by promoting AKT activation."

Acute Kidney Injury • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • Reperfusion Injury • WWC1

Sodium butyrate ameliorates muscle atrophy in type 2 diabetes-related sarcopenia via the PI3K/Akt/FoxO1 pathway. (PubMed, Tissue Cell) - "Research indicates that sodium butyrate attenuates type 2 diabetes-related sarcopenia via the activation of PI3K/Akt/FoxO1 signaling. Consequently, this short-chain fatty acid may serve as a viable intervention for patients suffering from sarcopenia in the context of type 2 diabetes."

Journal • Diabetes • Metabolic Disorders • Muscular Atrophy • Sarcopenia • Type 2 Diabetes Mellitus

Preclinical investigation of the potential synergistic action of small molecule inhibitors in combination with chemotherapy in colon and liver cancer cells (ESMO-TAT 2026) - "MK2206, an AKT inhibitor, and Navitoclax, a Bcl-2 inhibitor can promote apoptotic signaling and potentially overcome resistance mechanisms. Overall, AKT inhibition sensitized liver and colon cancer cells to cisplatin, highlighting a promising combination strategy."

Combination therapy • IO biomarker • Preclinical • Colon Cancer • Liver Cancer • Oncology • Solid Tumor • ANXA5 • BCL2L1 • BIRC5

Disrupting Akt-Wnt/β-catenin signaling suppresses glioblastoma stem cell growth and tumor progression in immunocompetent mice. (PubMed, J Neurooncol) - "In summary, MK-2206 outperformed iCRT3 efficacy in vitro, and suppressed GBM progression, in vivo. These findings suggest that Akt inhibition via MK-2206 may offer a promising therapeutic strategy for treating GBM, characterized by dysregulation of PI3K/Akt or Wnt/β-catenin pathways."

Journal • Preclinical • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

Targeting Soluble VCAM1 and GSK3β Improves Cerebrovascular Function and Reduces Stroke Pathology in Diabetic Mice. (PubMed, Cells) - "In contrast, pharmacological inhibition of Akt with MK2206 activated Glycogen Synthase Kinase 3 beta (GSK3β) and increased MC degranulation without affecting HDC expression. Neutralizing VCAM1 with a monoclonal antibody reduced circulating sVCAM1 and histamine levels, and, together with the GSK3β inhibitor Tideglusib, stabilized MCs, normalized cerebral artery tone, and reduced post-MCAO infarct size and edema. These findings identify two distinct yet complementary mast cell pathways in T2D, highlight an immune-vascular interface that drives cerebrovascular dysfunction, and propose sVCAM1 blockade plus GSK3β inhibition as rational strategies to protect cerebral vascular function in the diabetic brain."

Journal • Preclinical • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • GSK3B • HDC • HRH2 • VCAM1

Eccentric treadmill training and skeletal muscle immunometabolic responses in HFD-induced insulin resistance. (PubMed, Front Immunol) - "These effects were abolished by MK2206. Moderate-intensity eccentric treadmill training ameliorates HFD-induced skeletal muscle IR, likely driven by AKT-mediated reduction in pro-inflammatory M1 macrophage polarization."

Journal • Diabetes • CD86 • IL10 • MRC1 • SLC2A4

Indirubin suppresses ovarian cancer progression by inhibiting PI3K/AKT-mediated EMT and tumor growth without systemic toxicity. (PubMed, Phytomedicine) - "Indirubin exerts broad anti-ovarian cancer effects by inhibiting proliferation, migration, invasion as well as EMT, with demonstrated efficacy in xenograft models and no observed organ toxicity. Its mechanistic overlap with PI3K/AKT inhibitors underscores its potential as a multitargeted therapeutic agent."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CDH1 • CDH2 • VIM

IL-5 promotes airway remodeling in asthma by mediating epithelial-mesenchymal transition via the AKT/NLRP3 pathway. (PubMed, Int Immunopharmacol) - "Anti-IL-5 mAb reverses airway remodeling, with early low-dose treatment showing superior to late high-dose. It also better restores large airway function and provides comparable small airway improvement to late high-dose. Mechanistically, IL-5 promotes EMT via AKT/NLRP3 signaling, which is effectively suppressed by anti-IL-5 mAb early treatment."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CDH1 • CDH2 • IL5 • NLRP3

Ginkgetin alleviates UV-induced skin photoaging by reducing oxidative stress and promoting DNA repair via AKT-mediated homologous recombination repair. (PubMed, J Photochem Photobiol B) - "GK may serve as a potential therapeutic candidate for UV-induced photoaging by virtue of its dual capacity to scavenge ROS and enhance AKT-mediated DNA repair."

IO biomarker • Journal • Dermatitis • Oncology • BCL2 • BRCA2 • HRD • MMP1 • MMP2 • RAD51

Regulation of the AKT/Wnt/β-catenin Pathway and Induction of Cuproptosis by Curcumin in Glioblastoma. (PubMed, J Vis Exp) - "A172 and U251 cells were treated with CUM, AKT inhibitor MK-2206, Wnt inhibitor LGK974, and Elsm-Cu (Elesclomol + CuCl2). In nude mice, CUM significantly reduced tumor growth, promoted cuproptosis, and inhibited AKT/Wnt/β-catenin axis activation. Our results indicate that CUM suppresses AKT/Wnt/β-catenin signaling, promotes cuproptosis, and interferes with GBM progression."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Activation of TMEM175 lysosomal ion channels by CysLT1 receptor antagonists. (PubMed, Am J Physiol Cell Physiol) - "DCPIB, zafirlukast, and pranlukast activated TMEM175 independently of AKT activation, whereas the AKT inhibitor MK2206 partially inhibited montelukast-dependent TMEM175 activation. Not only did T119A and H449A mutations decrease apparent potencies of DCPIB, zafirlukast, and montelukast, but the T119A mutation produced a constitutively open channel phenotype. This study adds zafirlukast to the short list of moderately potent TMEM175 activators and identifies a region of the channel that contributes to activation gating."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

The mechanism study of isoorientin regulating neuroinflammation after subarachnoid hemorrhage through AKT/GSK3β. (PubMed, Int Immunopharmacol) - "This study provides compelling evidence that isoorientin exerts neuroprotective effects by regulating the AKT/GSK3β pathway, which may play a crucial role in mitigating neuroinflammation and neurological dysfunction after SAH. Isoorientin holds promise as a valuable therapeutic candidate for SAH treatment."

Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • GSK3B • IL10 • IL1B • IL4 • IL6 • MRC1 • TNFA

Evaluating PTEN mutations as a predictor of response to combinatorial therapy in ovarian cancer (LCC 2026) - "Cell growth assays indicated that combinatorial therapies with the PARP inhibitor Olaparib, plus PI3K pathway inhibitors including PI3K inhibitor BYL-719 or AKT inhibitor MK-2206, were more efficacious than monotherapies in suppressing cell growth. To extend the relevance of our studies, we will next use patient-derived OC organoids, as a more physiological model. We will provide further evidence regarding the efficacy of PARP plus PI3K inhibition for OC treatment and aim to identify additional predictors of sensitivity."

Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2 • PIK3CA • PTEN

Prioritizing PI3K pathway inhibitors for PTEN-mutant breast cancer (LCC 2026) - "Consistent with this, our lab previously demonstrated that mammary organoids harboring PTEN and PI3K mutations were resistant to BYL719 yet remained sensitive to AKT inhibition (via MK2206), underscoring a unique dependency of these cells to the oncogenic signal initiated by AKT (1). Turner, NC et al. (2023) 'Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer', The New England Journal of Medicine, 388 (22)."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • PTEN

CCDC137 affects sorafenib resistance in hepatocellular carcinoma cells by activating the AKT/mTOR signaling pathway. (PubMed, Clin Transl Oncol) - "Through triggering the Akt/mTOR signaling pathway, CCDC137 encourages sorafenib resistance in HCC cells, potentially offering a treatment approach to combat sorafenib resistance in HCC cells."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor

Phase II Randomized Study of MK-2206 and Bicalutamide in Prostate Cancer Patients With Rising PSA After Primary Therapy (ECOG-ACRIN E2809). (PubMed, Prostate) - P2 | "The results suggest that latent improved outcome of high-risk BCR patients (mean PSA doubling time 4.4 months) on combined MK-2206+Bic versus Bic alone was attributable to a subgroup identified by crosstalk AR activation secondary to inhibition of AKT. Toxicity may affect tolerance of sustained AKT-AR inhibition."

Journal • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

AKT signaling in hepatocytes rapidly increases glucose phosphorylation and contribution to glycogen without affecting metabolite pool sizes or glycogen breakdown. (PubMed, bioRxiv) - "Stable isotope tracing using [U- 13 C]-glucose was coupled with pharmacological inhibition of AKT using MK-2206 in primary rat hepatocytes...This was accompanied by a decrease in glucose contribution to glycogen, independent of changes to glycogen breakdown or glycogen synthase phosphorylation. Together, these results demonstrate that AKT acutely regulates glucose contribution to glycogen and its upstream precursors, suggesting a transcription-independent, glucokinase-centered mechanism for glycogen synthesis through the direct pathway."

Journal

Pathologic complete response (pCR) rates for HR+/HER2- breast cancer by molecular subtype in the I-SPY2 Trial. (ASCO 2022) - P2 | "Investigational agents are given with control weekly paclitaxel x 12, followed by AC x 4...For MK2206, BP Luminal pts were more likely to achieve pCR... Our data suggest that MP2 and BP Basal signatures identify a subset of HR+/HER2- BC more likely to respond to neoadjuvant therapy; and that an immune signature can identify pts more likely to respond to pembrolizumab. These findings will aid in guiding prioritization of targeted agents with the goal to optimize pCR for all pts."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival. (PubMed, Ann Oncol) - "Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival."

Clinical • Journal • Breast Cancer • Oncology • Solid Tumor

AKR1C3 promotes aerobic glycolysis in hepatic stellate cells via the AKT/mTOR pathway to induce liver fibrosis. (PubMed, Cell Signal) - "In addition, AKR1C3 overexpression promoted aerobic glycolysis in HSCs by activating the AKT/mTOR pathway, but these effects were partly reversed by glycolysis inhibitors (2-DG) and AKT inhibitors (MK-2206). Our findings revealed the mechanism by which AKR1C3 promotes LF, suggesting that AKR1C3 may serve as a potential therapeutic target for LF, warranting further studies."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Oncology • AKR1C3