MK-2206 / Merck (MSD) - LARVOL DELTA

A perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged AML (ASH 2025) - "Finally, we established the Myeloid Program as a predictive biomarker whose low activity scoreidentifies a vulnerable, undifferentiated state with unique sensitivity to PI3K/AKT/mTOR pathwayinhibitors (e.g., Selumetinib, r = -0.37, p = 2.2e-16; MK-2206, r = -0.31, p = 1.2e-11; Rapamycin (r = -0.34, p = 8.44e-14). Our work establishes circuit-level epigenetic compensation as a core mechanism ofresistance in KMT2A-r AML. We identify the Myeloid Program as a central regulatory node, a dual-purpose biomarker, and a key therapeutic objective. These findings provide a data-driven rationale fortwo distinct precision strategies: 1) collapsing the compensatory repressive circuit with synergistic co-inhibition of its core components, or 2) exploiting the emergent vulnerability of the undifferentiatedstate by combining differentiation agents with PI3K/mTOR pathway inhibitors."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • DOT1L • KAT6A • KMT2A

Inhibition of protein kinase C activity enables mineralization of senescent dental follicle cells with almost no osteogenic differentiation potential. (PubMed, Arch Oral Biol) - "Our results suggest that the addition of GÖ6976 is an efficient method to induce biomineralization in senescent DFCs."

Journal • SOST

Autophagy regulates MK-2206-induced LDL receptor expression and cholesterol efflux pathways. (PubMed, PLoS One) - "Both pharmacological and genetic impairment of autophagy attenuate the LDLR-inducing effects of MK-2206, supporting a role for autophagy in the regulation of cholesterol metabolism. The substantial reduction of ABCA1 expression in autophagy-deficient cells further indicates that autophagy is involved in cholesterol efflux regulation."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • ABCA1 • ATG7 • MAP1LC3B • SQSTM1

Host angiogenic reprogramming by Echinococcus multilocularis protoscoleces protein via PDGFR/PI3K/AKT cascade. (PubMed, Front Microbiol) - "Interventions utilizing a range of inhibitors at the in vitro level, including the PDGFR-β inhibitor AG1296, the PI3K inhibitor LY294002, the AKT inhibitor MK2206, and the FAK inhibitor Y15, demonstrated that E. multilocularis protoscoleces protein (EmP) induces angiogenesis through PDGFR/PI3K/AKT/FAK signaling pathway. Our findings provide new perspectives on how E. multilocularis infection triggers pathological angiogenesis in the host liver, and may provide a novel anti-angiogenic therapeutic strategy against E. multilocularis infection."

Journal • Infectious Disease • Oncology • PDGFRB

Machine learning-driven glycolytic subtyping and exosome-based PKM splicing modulation overcome drug resistance in hyper-glycolytic myeloid leukemia. (PubMed, NPJ Digit Med) - "These subtypes exhibited distinct drug sensitivities (C1 sensitive to panobinostat, MK-2206, 17-AAG; C2 sensitive to venetoclax) and predicted immunotherapy responses (C1 potentially benefiting more from anti-PD-1)...Crucially, aberrant PKM2 overexpression was linked to imatinib (IM) resistance...To mitigate vMO toxicity, IL3-Lamp2b-engineered exosomes were developed, demonstrating efficient vMO loading, targeted delivery to leukemia cells, potent PKM splicing correction, significant IM resistance reversal, and minimal stromal cell toxicity. This work defines glycolysis-based AML subtypes with therapeutic implications and establishes engineered exosome-delivered vMO as a promising strategy to overcome drug resistance in hyper-glycolytic myeloid leukemia."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HIF1A • PKM

Butyrate regulates the blood-brain barrier transport and intra-endothelial accumulation of Alzheimer's disease Amyloid-beta peptides. (PubMed, bioRxiv) - "The roles of various molecular mediators were confirmed using specific inhibitors (MK2206, Trametinib, Rapamycin, VX-745). These changes may also improve the integrity of BBB tight junctions by increasing claudin-5 expression and extracellular matrix, and by upregulating TIMP-2 expression. This study highlights butyrate's potential as a therapeutic modulator of AD-related BBB dysfunction."

Journal • Alzheimer's Disease • CNS Disorders • Aβ42 • CLDN5 • TIMP2

Hybrid Dihydropyrimidinones Targeting AKT Signaling: Antitumor Activity in Hormone-Dependent 2D and 3D Cancer Models. (PubMed, Pharmaceutics) - "Combinatorial effects with hormone therapies (tamoxifen, fulvestrant, and letrozole) and the AKT inhibitor MK2206 were evaluated. Xanthene- and pyran-based hybrids-particularly SJ028, SJ064, and SJ078-showed strong antitumor activity through apoptosis induction, cell cycle arrest, and PI3K/AKT pathway modulation. Their preserved efficacy in resistant models and synergistic interactions with hormone therapies contrasted with the antagonism observed with AKT inhibition, highlighting their potential as promising candidates for the treatment of hormone-responsive and -resistant cancers."

Journal • Preclinical • Breast Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • CASP3 • CASP7

Role of TRPV6-Mediated Calcium Signaling in High-Glucose-Inhibited Keratinocyte Migration. (PubMed, FASEB J) - "The calmodulin inhibitor W-7 or TFP suppressed the TRPV6 overexpression-induced increases in FN1 expression and cell migration, whereas the Akt inhibitor LY294002 or MK2206 restored the TRPV6 overexpression-induced increases in FN1 expression and cell migration to control levels in keratinocytes. Taken together, these results indicated that high glucose inhibits the expression of TRPV6 in keratinocytes, decreases Ca2+ flow into these cells, and decreases FN1 expression via Ca2+-calmodulin and Akt signaling to inhibit keratinocyte migration. Thus, TRPV6 may be a potential target for the development of novel treatments in diabetes-induced impaired wound healing."

Journal • Diabetes • Metabolic Disorders • FN1 • TRPV6

TTC36-Mediated Tumor Suppression via YBX3/SPRED1 Axis Paradoxically Reduces Sorafenib Sensitivity in Hepatocellular Carcinoma. (PubMed, Int J Biol Sci) - "Akt inhibition (MK-2206) reverses sorafenib resistance in TTC36-high HCC. Paradoxically, TTC36-high HCC develops sorafenib resistance through PI3K/Akt hyperactivation, which is overcome by combined Akt inhibition. Thus, TTC36 may serves as a predictive biomarker to stratify HCC patients for personalized therapy: sorafenib monotherapy for TTC36-low tumors and sorafenib-Akt inhibitor combination for TTC36-high, sorafenib-resistant tumors."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Revealing the Synergistic Potential of Mosunetuzumab Plus Polatuzumab Vedotin through CD20 Upregulation (ASH 2024) - "Background Despite the development of effective therapies for aggressive non-Hodgkin lymphoma, such as polatuzumab vedotin (Pola) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP), approximately 20–40% of patients experience relapsed or refractory disease after first-line treatment...Treatment of AKT and MEK inhibitors (MK-2206 [0.5 µM] and U0126 [10 µM]) reduced the synergistic combination effect of Mosun plus Pola in these cells...Our data suggest the possibility that Pola-induced upregulation of CD20 expression contributes to the synergy of this combination. From these findings, we identified a potential molecular rationale for the combined use of Mosun plus Pola, providing further supporting data for the effectiveness of this regimen."

B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • AKT1 • CD20 • CD4 • CD69 • CD79B • CD8 • IL2

High Glucose- and Adenine-Induced Endothelial Dysfunction Involves Activation of the cGAS-STING Signaling Pathway and Suppression of Endothelial Nitric Oxide Synthase (eNOS) (KIDNEY WEEK 2025) - "PI3K inhibition (LY294002) and Akt inhibition (MK-2206) suppressed these phosphorylation events and significantly reduced HG-induced hypertrophy and matrix protein accumulation...Modulation of mTORC1 activity via rapamycin or constitutively active mTORC1 expression confirmed mTOR-dependent regulation of cGAS–STING signaling...Conclusion These findings suggest that hyperglycemia-induced endothelial dysfunction is mediated via the HG-MTAP-adenine-PI3K–Akt–mTOR–cGAS–STING axis. Targeting this pathway may offer therapeutic benefit in preventing or reversing endothelial dysfunction in DKD."

Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Nephrology • Renal Disease • MTAP • NOS3

Cancer Pathway Connectivity Resolved By Drug Perturbation and RNA Sequencing (ASH 2024) - "We selected 108 CLL patient samples with genetic annotation and exposed them ex-vivo to small-molecule inhibitors used clinically (ibrutinib/BTKi, duvelisib/PI3Ki, trametinib/MEKi, everolimus/mTORi, selinexor/XPO1i) or targeting key signaling pathways (compound 26/TLRi, MK2206/AKTi, nutlin-3a/MDM2i, IBET872/BETi) for 48h. In conclusion, the addition of targeted pathway perturbations to the GEP of primary CLL samples can greatly enhance the potential for molecular and functional classification of disease and subgroups. Our study provides a blueprint to use perturbed omics profiling and interaction testing to link disease drivers to pathway activation and function."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • MYC • TNFA • ZAP70

Exosomal microRNA-20b-5p contributes to cytarabine resistance in acute myeloid leukemia via the microtubule-associated serine/threonine kinase-like-phosphatidylinositol 3-kinase-protein kinase B signaling axis. (PubMed, Int J Biol Macromol) - "Exosomal miR-20b-5p represses MASTL, remodels PI3K-AKT, and attenuates Ara-C responses in AML models. Seed-mutant reporters and 3'-UTR-independent rescue support target specificity. Findings are mechanistic and hypothesis-generating; clinical relevance requires confirmation in primary blasts and prospective validation."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • MIR20B

Xihuang Wan mediates glycolysis and inhibits lung cancer development by downregulating the AKT/STAT3 pathway. (PubMed, Tissue Cell) - "To further investigate the underlying mechanism, cells were treated with the AKT activator SC79 and AKT inhibitor MK-2206...Additionally, XHW obviously reduced glycolysis-related and AKT-STAT3 pathway protein expression. In conclusion, these findings revealed that XHW inhibits glycolysis in lung cancer by downregulating AKT-STAT3 pathway."

Journal • Lung Cancer • Oncology • Solid Tumor

Discovery and characterization of AKT1-E17K mutant-selective inhibitors for the treatment of AKT1-E17K mutant cancers (AACR-NCI-EORTC 2025) - "In an AKT1-E17K-expressing ER+ BC CDX model (CRISPR MCF7-AKT1-E17K), VVD-4009 (30 mg/kg QD) combined with fulvestrant achieved tumor regression without inducing hyperglycemia, a dose-limiting toxicity observed with the capivasertib/fulvestrant combination...In contrast to alpelisib, MK-2206, and capivasertib, VVD-4009 preserved skin barrier integrity...In summary, we have developed potent and highly selective AKT1-E17K inhibitors that demonstrate superior in vivo efficacy in AKT1-E17K-driven models compared to capivasertib. These findings underscore the value of high mutant selectivity combined with optimized PK for effectively treating aggressive, refractory AKT1-E17K mutant cancers."

Gynecologic Cancers • Oncology • Triple Negative Breast Cancer • AKT1 • AKT2 • ER • PAK2

Medicarpin reduces cisplatin resistance and causes apoptosis by inhibiting the AKT/Bcl2 pathway in breast cancer. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "However, the AKT inhibitor MK2206 increased the effect of Med, further inhibited the malignant progression of BC cells, and induced cellular DNA damage and cycle arrest. The effect of the combined treatment of the two was higher than single treatment, indicating that Med could improve the therapeutic efficacy of Cis and reduce the drug resistance of CisR-MCF-7 cells. Med inhibits BC malignant biological behavior and reduces Cis resistance by blocking the AKT/Bcl2 pathway."

Journal • Breast Cancer • Oncology • Solid Tumor

Integrated metabolomic and transcriptomic analysis identifies adipogenic differentiation of mesenchymal stem cells as a driver of chemoresistance in acute myeloid leukemia. (PubMed, J Exp Clin Cancer Res) - "This work demonstrates that the adipogenically differentiated MSCs enhance the survival and chemoresistance of AML cells by modulating metabolic and signaling pathways. It provides integrated insights into the microenvironment-driven mechanisms of AML drug resistance and presents potential therapeutic targets to enhance treatment efficacy."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • IL6

The Combined Treatment of 4EGl-1 and MK-2206 Inhibits Nasopharyngeal Carcinoma Progress by Inducing Autophagy. (PubMed, FASEB J) - "The in vitro results were confirmed with in vivo mouse models. 4EGI-1 strongly inhibited NPC growth and metastasis, and 4EGI-1 may develop as the potential therapy for the treatment of metastatic NPC."

Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • EIF4E • EIF4G1

The role of AKT inhibitors combined with Ruxolitinib in ameliorating myeloproliferative disorders in mice with CALR gene mutations (PubMed, Zhonghua Xue Ye Xue Za Zhi) - "④ Histopathological analysis (H&E staining) of bone marrow and spleen tissues confirmed that the combined regimen decreased both tumor cell infiltration and the proportion of abnormal megakaryocytes in these organs. The combination of AKT inhibitor MK2206 and Ruxolitinib is effective at significantly ameliorating disease symptoms and reducing tumor infiltration in vivo in mice with a myeloproliferative tumor transplantation driven by a CALR gene mutation."

Journal • Preclinical • Myeloproliferative Neoplasm • Oncology • Transplantation • CALR

The study of beneficial effect and mechanism of propofol on TNF-α-induced p-Tau increase in HT22 hippocampal neurons. (PubMed, Neuroscience) - "Propofol may attenuate TNF-α-induced p-Tau expression in HT22 cells through modulation of the AMPK/AKT signaling pathway, and may inhibit TNF-α-enhanced mitophagy by affecting the AMPK/SIRT3 signaling pathway."

Journal • Inflammation • SIRT3 • TNFA

ATP1B4 as a Candidate Upstream Regulator of Muscle Atrophy in Diabetic Sarcopenia via PI3K/AKT/mTOR-Mediated Autophagy. (PubMed, Int J Biochem Cell Biol) - "ATP1B4 may aggravate diabetic sarcopenia by acting as an upstream suppressor of the PI3K/AKT/mTOR pathway."

Journal • Diabetes • Muscular Atrophy • Sarcopenia • MFN2

FOXK1 regulates apoptosis, migration and angiogenesis in high glucose-induced vascular endothelial cells through p-AKT/AKT signaling pathway. (PubMed, BMC Biotechnol) - "FOXK1 may mediate vascular endothelial dysfunction in DR by inhibiting p-AKT/AKT pathway."

Journal • Diabetes • Diabetic Retinopathy • Oncology • Retinal Disorders

Analysis of the Stimulative Effect of Arginine on Translation Initiation of Protein Synthesis in Skeletal Muscle. (PubMed, Nutrients) - "Although the detailed mechanism by which Arg regulates protein synthesis is not fully known, it is believed to occur primarily through the mechanistic target of rapamycin complex 1 (mTORC1)-dependent activation of translation initiation. In addition, pretreatment with the PI3K inhibitor LY294002, the AKT inhibitor MK-2206, and the GPRC6A antagonist calindol completely inhibited Arg-upregulated 4E-BP1 and S6K1 phosphorylation. The findings of this study suggest that Arg stimulates the initiation of mRNA translation via the GPRC6A/PI3K/AKT/mTORC1 signaling pathway, thereby stimulating protein synthesis in skeletal muscle."

Journal • EIF4EBP1 • GPRC6A

Mesenchymal Stem Cell Derived Exosomes Alleviates Hirschsprung-Associated Enterocolitis by Inhibiting AKT Phosphorylation in Macrophages Through miR-223. (PubMed, Stem Cells Int) - "MSCs, MSC derived exosomes, miR-223, or MK2206 were added to macrophages, and the levels of miR-223 in macrophages after exosome treatment were measured by RT-qPCR...MSCs derived exosomes reduce enterocyte death by suppressing AKT phosphorylation and IL-1β secretion via miR-223, and subsequently mitigate HAEC in mice. These findings suggest that MSC-derived exosomes, particularly those enriched in miR-223, may serve as a promising therapeutic strategy for the prevention or treatment of HAEC."

Journal • Gastrointestinal Disorder • Inflammation • Inflammatory Bowel Disease • CD68 • EDNRB • IL1B • MIR223

Yiqi Xugu HeJi restores cartilage metabolic homeostasis via AKT1-Thr473 activation in osteoarthritis. (PubMed, Phytomedicine) - "YQXGHJ mitigates OA progression by reestablishing cartilage metabolic balance through the activation of the PI3K/AKT signaling pathway, specifically enhancing AKT1-T473 phosphorylation. This study provides a pharmacological and mechanistic foundation for the clinical use of YQXGHJ in treating OA."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • COL2A1 • IL1B • IL6 • MMP13 • SOX9