OTS167 / OncoTherapy - LARVOL DELTA

Combination of a novel MELK inhibitor with standard of care treatment results in tumor regression and improved survival in a triple-negative inflammatory breast cancer xenograft model. (SABCS 2025) - "Materials and Methods We evaluated the efficacy and toxicity of MELK-inhibitors (MELK-In-17, MELK-In-30e, and OTS167), alone or in combination with paclitaxel or eribulin, using the 4T1(TNBC) and SUM149 (TN-IBC) mouse models. These findings provide a rationale for further investigation into MELK-targeted combination therapies to enhance the efficacy of existing therapies and immune activation in aggressive cancers. We plan to assess the prognostic value of MELK, EMT, and immune markers based on mIF analysis of patient samples."

IO biomarker • Preclinical • Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD163 • CDH1 • CDH2 • FN1 • MELK • MRC1 • PD-L1 • VIM

Melk facilitates pulmonary artery smooth muscle cell proliferation and migration in pulmonary hypertension via modulation of YAP/TAZ signaling. (PubMed, Front Cell Dev Biol) - "The YAP inhibitor Verteporfin blunted MELK-driven PASMC proliferation and migration, underscoring the central role of YAP/TAZ signaling. Finally, in vivo pharmacological inhibition of MELK by OTS167 markedly reduced right ventricular systolic pressure, hypertrophy, and pulmonary vascular remodeling in Su/H mice, confirming the therapeutic relevance of MELK targeting in PAH. Collectively, these findings identify MELK as a novel regulator of PASMC pathobiology in PAH and suggest that it may represent a potential therapeutic target."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • AMPK • BIRC5 • CCN1 • CCND1 • CTGF • MELK • PCNA

Small molecule OTS167 increases erythropoiesis and improves anemia in diamond blackfan anemia models in vitro and In Vivo (ASH 2025) - "Even if the drug targeting NLK does not completely rescue the anemia inhuman and mouse models of DBA, the improvement could be enough to sufficiently raise thehemoglobin to prevent the need for chronic red cell transfusions or steroid treatment. We propose thatOTS167 and other NLK inhibitors are promising approaches to treat DBA."

Preclinical • Anemia • Aplastic Anemia • Genetic Disorders • Graft versus Host Disease • Immunology • Infectious Disease • MELK • RPL11

Safety Study of MELK Inhibitor to Treat Patients With Advanced Breast Cancer and Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: OncoTherapy Science, Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

Small Molecule Inhibitor Targeting Nemo-like Kinase Improves Erythropoiesis in Human and Mouse Models of Diamond Blackfan Anemia (ASH 2023) - "We confirmed that NLK activity was increased in erythroid progenitors from the Rpl11-haploinsufficient mice for in vitro phosphorylation of the substrate compared with tamoxifen-treated wild type mice...We have initiated studies to test the efficacy of OTS167 in vivo using Rpl11-haploinsufficient mouse models. Given that DBA is associated with a number of mutations in the ribosome, using one drug that targets NLK as a common therapeutic target could be a more practical treatment option for patients in contrast to gene therapy or gene editing followed by autologous stem cell rescue. Even if the drug targeting NLK does not completely rescue the anemia in ribosome-insufficient cell models of DBA, the improvement could be enough to help patients especially in combination with other drugs that are currently being used or studied."

Preclinical • Anemia • Aplastic Anemia • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Infectious Disease • CD34 • MELK • RPL11 • TFRC

OTSSP167 suppresses TNBC brain metastasis via ROS-driven P38/JNK and FAK/ERK pathways. (PubMed, Eur J Pharmacol) - "ROS scavenging via N-acetylcysteine (NAC) reverses these effects, confirming ROS as the central mediator of antitumor activity of OTSSP167. These findings unveil a redox-centric mechanism by which OTSSP167 disrupts TNBC progression, positioning it as a promising therapeutic candidate for combating TNBC BM. The study underscores the translational relevance of targeting MELK and ROS-dependent kinase networks to address unmet clinical needs in TNBC management."

Journal • Oncology • Solid Tumor • Triple Negative Breast Cancer • MAPK8 • MELK

Screening kinase inhibitors identifies MELK as a prime target against influenza virus infections through inhibition of viral mRNA splicing. (PubMed, Front Microbiol) - "Finally, we demonstrated that combining OTS167 with zanamivir or oseltamivir resulted in additive antiviral activity. In conclusion, we identified MELK as a crucial host kinase that supports the influenza virus infection. OTS167, a pharmacological inhibitor of MELK currently undergoing phase II clinical trials for treating cancer, potently inhibits influenza virus infections in vitro and in mice, representing a promising lead for developing novel influenza antivirals."

Journal • Infectious Disease • Influenza • Oncology • Pneumonia • Respiratory Diseases • CDK1 • MELK

Safety Study of MELK Inhibitor to Treat Patients with Advanced Breast Cancer and Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=70 | Active, not recruiting | Sponsor: OncoTherapy Science, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2024 ➔ Sep 2027 | Trial primary completion date: Aug 2024 ➔ Sep 2027

Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

Bmal1-mediated circadian MELK expression potentiates MELK inhibitor chronotherapy for esophageal cancer. (PubMed, Mol Cancer Res) - "Furthermore, in nude mice with transplanted tumor, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • Transplantation • ARNTL • BMAL1 • CLOCK • MELK

MELK controls stromal components through fibronectin modulation in highly aggressive breast cancers. (SABCS 2024) - "To pave the path for clinical translation of MELK inhibitors, we evaluated three MELK inhibitors (MELK-In-17, MELK-In-30e, and OTS167) to find the inhibitor with the highest efficacy and lowest toxicity alone or in combination with paclitaxel in the murine TNBC 4T1 mouse model. Conclusions and Future Directions Our results showed that MELK promotes FN1 expression, which may be involved in stromal reorganization and contribute to tumor progression in TNBC. Currently, we are evaluating MELK inhibitors with other rational combination therapies in a triple-negative IBC xenograft model."

Stroma • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • FN1 • HER-2 • MELK

MELK as a mediator of stemness and metastasis in aggressive subtypes of breast cancer (SABCS 2024) - "Genetic knockdown of MELK was achieved using doxycycline-inducible shRNAs or stable siRNA expression, while pharmacologic knockdown was conducted using the MELK inhibitor OTSSP-167...Confirmatory studies re underway in other subtypes of breast cancer. These results highlight the potential of targeting MELK as a therapeutic strategy to mitigate breast cancer metastasis and improve patient outcomes."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • MELK • PGR

Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy. (PubMed, Mol Cancer) - "Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC."

Journal • Tumor cell • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CCL2 • CD8 • MELK

PKN1 is a Novel Therapeutic Target to Promote Graft Survival (ATC 2024) - "*Purpose: The study objective is to identify protein kinase N1 (PKN1) as a novel therapeutic target to promote graft survival.* Our group was the first to demonstrate that targeting JAK1/2 using small molecule inhibitors, baricitinib (BARI) and ruxolitinib (RUX), prevents and treats graft-vs-host disease (GvHD) while enhancing multi-lineage hematopoietic reconstitution and graft-vs-leukemia (GvL) effect in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT)...Furthermore, BARI combined with cyclosporin A (CsA) completely protected allogeneic skin and heart grafts from rejection as long as the combination of BARI and CsA was administered...To narrow down the candidates for more focused investigation, we examined if OTS167, a PKN1 inhibitor, alters the downstream signaling of these candidate pathways... All of these data support our hypothesis that PKN1 is a novel therapeutic target to prevent graft rejection. We have recovered PKN1fl/fl mice from..."

Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplant Rejection • Transplantation • JAK1 • RPH3A • S1PR1

AI identifies potent inducers of breast cancer stem cell differentiation based on adversarial learning from gene expression data. (PubMed, Brief Bioinform) - "Experimental validation in MDA-MB-231 and MCF7 cells demonstrated the efficacy of five out of six tested molecules among those scored highest by the model. In particular, the efficacy of triptolide, OTS-167, quinacrine, granisetron and A-443654 offer a potential avenue for targeted therapies against breast CSCs."

Cancer stem • Journal • Breast Cancer • Oncology • Solid Tumor

Therapeutic targeting of MELK using a drug repurposing approach to combat TNBC cells (AACR 2024) - "Evidence suggests that the existing inhibitor for MELK (OTSSP167) has shown poor specificity... The present study opens the avenue for using repurposed drugs as potential therapeutic molecules against MELK activity to combat TNBC progression."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MELK

Targeting MELK improves PD-1 blockade efficiency in cervical cancer via enhancing antitumor immunity. (PubMed, Mol Ther Oncol) - "Finally, MELK overexpression conferred tolerance to PD-1 blockade in cervical tumors, whereas targeting MELK by OTSSP167 significantly enhanced PD-1 blockade efficiency. Our data elucidated a novel role of MELK in regulating Th1/Th2 balance and anti-PD-1 immunotherapy in cervical cancer."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • CD8 • IL4 • IL6 • MELK

Exploration of MELK as a downstream of Del-1 and druggable targets in triple-negative breast cancer. (PubMed, Breast Cancer Res Treat) - "We found that MELK acts downstream of Del-1 and is a promising druggable target, especially in basal-like and mesenchymal stem-like subtype."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EDIL3 • MELK

Prostate cancer progression relies on the mitotic kinase citron kinase. (PubMed, Cancer Res) - "CIT kinase activity was identified as druggable and was potently inhibited by the multi-kinase inhibitor OTS-167, which decreased proliferation of treatment-resistant PCa cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant PCa. These findings provide insights into regulation of aggressive PCa cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of PCa progression."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • E2F2 • SKP2

p53 isoform expression promotes a stemness phenotype and inhibits doxorubicin sensitivity in breast cancer. (PubMed, Cell Death Dis) - "Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting Δ40p53 in tumours that have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin."

Journal • Breast Cancer • Oncology • Solid Tumor • MIR145 • MIR200 • NANOG • POU5F1 • SOX2

Effect of MELK Inhibitor OTSSP167 on Diffuse Large B-Cell Lymphoma (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi) - "The MELK inhibitor OTSSP167 can inhibit the proliferation and promote the apoptosis of DLBCL cells by inhibiting the expression of cycle-related proteins and anti-apoptosis-related proteins."

IO biomarker • Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • BCL2 • BCL2L1 • CASP3 • CASP7 • CCNA2 • CCNB1 • CCNE1 • CDK1 • MELK

MELK and Del-1 as druggable targets in TNBC. (ASCO 2023) - "OTS167 was treated for inhibition of MELK... In this study, we sought to investigate the association between De1-1 and MELK in TNBC cell lines and tumor tissue. We found that MELK is downstream of del-1 and is a promising target, especially in the basal-like 1 subtype. Further research is warranted."

HER2 Breast Cancer • HER2 Positive Breast Cancer • Immune Modulation • Triple Negative Breast Cancer • AR • EDIL3 • MELK

PKN1 is a novel therapeutic target to prevent graft-vs-host disease after allogeneic hematopoietic cell transplantation (P1025) (IMMUNOLOGY 2023) - "We were the first to demonstrate that targeting JAK1/2 using baricitinib (BARI) and ruxolitinib (RUX) prevents and treats GVHD while enhancing multi-lineage hematopoietic reconstitution and graft-vs-leukemia (GvL) effect in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT)...To define the role of PKN1 in GvHD, we examined if OTS167, a PKN1 inhibitor, alters the downstream signaling of these candidate pathways...Furthermore, we found that allo-HCT recipient mice transplanted with S1PR1 KO T cells demonstrate significantly improved overall survival (p<0.05). These data suggest that PKN1 and S1PR1/PPP1R14A (and also LFA-1/STK4 which is currently under investigation) are critical components in inducing GvHD."

Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation • JAK1 • RPH3A • S1PR1

Maternal embryonic leucine zipper kinase in tumor cell and tumor microenvironment: Emerging player and promising therapeutic opportunities. (PubMed, Cancer Lett) - "In this review, we outline the structural features, molecular biological functions, potential regulatory mechanisms and important roles of MELK in tumors and tumor microenvironment, as well as substances targeting MELK. Although many molecular mechanisms of MELK in the process of tumor regulation are still unknown, it is worth affirming that MELK is a potential tumor molecular therapeutic target, and its unique superiority and important role provide clues and confidence for subsequent basic research and scientific transformation."

Biomarker • Journal • Review • Tumor cell • Tumor microenvironment • Oncology • AMPK • MELK

IPA-3 (PAK1 inhibitor) or OTSSP167 (MELK inhibitor) plus auranofin (PKC inhibitor), a therapeutic option for EGFR mutant, KRAS mutant and squamous cell non-small cell lung cancer (NSCLC). (ASCO 2018) - P1; "To date there are no PAK1 inhibitors available. Phase I trials of OTSSP167 in breast cancer (NCT02926690) and leukemia are ongoing. Hence, the combination of OTSSP167 and auranofin could be effective and of interest to be tested in EGFR, KRAS mutant and squamous NSCLC patients."

Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Safety Study of MELK Inhibitor to Treat Patients With Advanced Breast Cancer and Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: OncoTherapy Science, Inc. | Trial completion date: Dec 2022 ➔ Aug 2024 | Trial primary completion date: Dec 2022 ➔ Aug 2024

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2