MBQ-167 / MBQ Pharma - LARVOL DELTA

Characterization of the Rac inhibitor CPV-337 in metastatic breast cancer (AACR 2025) - P1 | "Our lead compound MBQ-167, a dual Rac/Cdc42 inhibitor (IC50 of ~100nM; GI50 of 130nM), is currently in Phase I clinical trials for advanced triple-negative breast cancer (NCT06075810)...Interestingly, a significant increase in M1 anti-tumorigenic macrophages was observed in splenocytes of mice treated with CPV-337, implicating CPV-337 in the anticancer immune response. Further evaluation of CPV-337's inhibitory mechanism, toxicity, bioavailability, and Rac/Cdc42 regulated processes in the tumor microenvironment are warranted to translate this promising anticancer compound to the clinic."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer • HER-2

Characterization of the RAC1/CDC42 inhibitor MBQ-167 to assess its utility as a tool for interrogating Rho GTPase biology (AACR 2025) - "Simulations helped understanding that MBQ-167 is not a specific inhibitor and therefore not adequate as a tool for interrogating the biology of interest. Further studies are needed to find additional inhibitors against RAC/CDC42 and to understand the effects of MBQ-167 on cancer cells and as a clinical asset tested in Phase I clinical trials as a single agent against advanced breast cancer."

Breast Cancer • Oncology • Solid Tumor • AURKA • CDK1 • MAPK14 • PLK1 • PLK2 • RAC1

Systematic Evaluation of GAPs and Gefs Identifies ARHGAP45 As a Targetable Leukemia-Specific Dependency (ASH 2024) - "Pharmacological inhibition of CDC42 with the CDC42/Rac1 inhibitor MBQ-167 further enhanced survival following ARHGAP45 KO in AML models...We find that ARHGAP45 is a bona fide GAP for RhoA that is selectively required in AML cells but dispensable in normal hematopoietic cells. Furthermore, we propose a novel immunotherapeutic strategy to target AML by augmenting new and existing TCR-T therapies against ARHGAP45-derived antigens."

IO biomarker • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Solid Tumor • CD34 • HLA-A • RHOA

A Study of Oral MBQ-167 in Participants With Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: MBQ Pharma | Trial completion date: Oct 2024 ➔ Oct 2025 | Trial primary completion date: Oct 2024 ➔ Oct 2025

Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Oncology • Solid Tumor

M6 metabolite enhances the efficacy of the Rac/Cdc42 inhibitor MBQ-167 in metastatic advanced breast cancer (SABCS 2024) - P1 | "Therefore, M6 is expected to significantly contribute to the duration and intensity of MBQ-167 efficacy in metastatic advanced breast cancer. This study was supported by the US Army Breast Cancer Research Program (BCRP) W81XWH2010041 and HT9425-23-1-0166 (to SD) and HT9425-23-1-0381 (to JFRO)."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP7 • CDC42 • HER-2

Testing the Rac/Cdc42 inhibitor MBQ-167 in ex vivo cultures of Hispanic TNBC tissue (SABCS 2024) - P1 | "The results of this study promise to directly address the dynamics of Rac/Cdc42 inhibitor therapy in Puerto Rican TNBC patients and forward Phase 2 trials for this novel therapeutic in advanced breast cancer patients. This study was supported by the US Army Breast Cancer Research Program (BCRP) HT9425-23-1-0166 (to SD), 5R25GM061151-21 (ATS), and NIH NCI 5R25CA240120-05 (MDT)."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Triple Negative Breast Cancer • HER-2

Synthesis of novel, covalent inhibitors of Rac/Cdc42 for the treatment of metastatic breast cancer (ACS-Fall 2024) - "Building on existing inhibitors EHop-016 andMBQ-167, recently CPV-337 was developed and found to be five times more potent than MBQ-167...This research is proposed to develop novel compounds with improved potency to address the urgent need for improved therapeutics for Stage IV breast cancer, focusing on disrupting metastasis at its initiation phase, invasion. Possible future works include exploring the in vivo efficacy and safety profiles of the optimized compounds in preclinical models."

Metastases • Breast Cancer • Oncology • Solid Tumor • CDC42 • RAC1

Novel inhibition of central carbon metabolism pathways by Rac and Cdc42 inhibitor MBQ-167 and paclitaxel. (PubMed, Mol Cancer Ther) - "Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ-167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ-167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action."

Journal • Breast Cancer • Hepatology • Oncology • Solid Tumor • Triple Negative Breast Cancer

Pharmacodynamic biomarkers for Rac and Cdc42 inhibitor efficacy (AACR 2024) - "These results demonstrate the potential of p-PAK and YKL-40/CHI3L1 from blood as biomarkers for Rac/Cdc42 inhibitor efficacy. This study impacts pharmacodynamic biomarker design for the planned Phase 2 clinical trials for MBQ-167 in breast and pancreatic cancer."

Biomarker • Clinical • PK/PD data • Breast Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CHI3L1 • IL6

Mechanisms by which the Rac & Cdc42 inhibitor MBQ-167 overcomes the adverse effects of paclitaxel in TNBC (AACR 2024) - "MBQ-167, but not PXL, reduced LPS-induced (i.e., TLR4-regulated) NfkB translocation to the nucleus, with a similar effect as the combination. Therefore, MBQ-167 may prevent PXL-induced metastasis by partially inhibiting the NF-kB pathway in TNBC tumors and reducing inflammation and immunosuppression from M1 and M2 macrophages in vivo."

Adverse events • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MRC1

Screening of Rac1 and Cdc42 inhibitors as anti-metastatic compounds (AACR 2024) - "Therefore, CPV-337 may have cytotoxic effects on breast cancer. We are continuing to screen the library of MBQ-167 derivatives in breast, pancreatic, lung, and prostate cancer cell lines."

Metastases • Breast Cancer • Genito-urinary Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • RAC1

Efficacy and delivery strategies of the dual Rac/Cdc42 inhibitor MBQ-167 in HER2 overexpressing breast cancer. (PubMed, Transl Oncol) - "When MBQ-167 was targeted to mammary fatpad tumors established from HER2 overexpressing cells via immunoliposomes functionalized with trastuzumab, MBQ-167 and MBQ-167-loaded liposomes show equal efficacy in reducing the viability of trastuzumab-resistant cells, inhibiting tumor growth in mouse xenografts, and reducing metastasis to lungs and liver. This study demonstrates the efficacy of MBQ-167 as an alternative therapeutic in HER2 overexpressing cancers, delivered either in free form or in liposomes."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Implication of Rac1 GTPase in molecular and cellular mitochondrial functions. (PubMed, Life Sci) - "Inhibitors of Rac1 have been identified (NSC-23766, EHT-1864) and some are being developed for the treatment of cancer (MBQ-167) or central nervous system diseases (JK-50561). Their effects on mtRac1 warrant further investigations. An overview of mtRac1 is provided here."

Journal • Review • Oncology • BCL2 • RAC1

MBQ Pharma announces the First-in-Human Dose for Advanced Breast Cancer with the dual targeted Rac/Cdc42 inhibitor: MBQ-167 (Issuer Direct) - "MBQ Pharma...is thrilled to announce a significant milestone. We are proud to announce that we have dosed the first participant in our Phase 1 clinical trial of MBQ-167. MBQ-167 is the first-in-class drug as a dual inhibitor designed to target two GTPase proteins: Rac and Cdc42. Overexpression of these proteins in cancer cells are considered the primary drivers of solid tumor cancer spread and of cancer cells developing resistance to treatment. MBQ Pharma has successfully initiated this trial for patients who need additional options after all possible standard cancer therapies have been attempted....This Phase 1 clinical trial is an open-label, dose-escalation study aimed at establishing the maximum tolerated dose (MTD) of MBQ-167."

Trial status • Breast Cancer

A Study of Oral MBQ-167 in Participants With Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: MBQ Pharma

Metastases • New P1 trial • Breast Cancer • Oncology • Solid Tumor

Rac and Cdc42 inhibitors reduce macrophage function in breast cancer preclinical models. (PubMed, Front Oncol) - "This was confirmed from splenocytes treated with lipopolysaccharide (LPS) where EHop-016 or MBQ-167 reduced IL-6 secretion in response to LPS. Rac/Cdc42 inhibition induces an antitumor environment via inhibition of both metastatic cancer cells and immunosuppressive myeloid cells in the TME."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • IL6

Targeting Rac/Cdc42 GTPases to overcome HER2-targeted therapy resistance (AACR 2023) - "Clinically, this problem has been tackled by targeting the HER2 receptor with antibodies (e.g., Trastuzumab, Pertuzumab) and (or) tyrosine kinase inhibitors (TKIs; e.g., Lapatinib). MBQ-167 reduced Rac activity and downstream signaling, as well as cell viability with a GI50 of 78nM after 72 hours, while caspase activity was increased after 24 hours of treatment. The results presented herein show the utility of the Rac/Cdc42 inhibitor MBQ-167 in overcoming HER2-targeted therapy resistance."

Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CDC42 • ER • PGR

Rac and Cdc42 inhibition on macrophage function in the pancreatic tumor microenvironment (AACR 2023) - "In addition, MBQ-167 reduced macrophage phagocytosis by 56% at 500nM. This study demonstrates the utility of Rac/Cdc42 inhibition to reduce pancreatic cancer progression in the TME."

Biomarker • Tumor microenvironment • Breast Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast cancer (AACR 2023) - "MBQ-167 in combination with Paclitaxel reduced the enhanced lung metastasis in response to Paclitaxel. In conclusion, this study validates the clinical testing of MBQ-167 in combination with Paclitaxel as a potential combination therapy for TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGFR • RAC1

The potential therapeutic effect of the Rac/Cdc42 inhibitor MBQ-167 in glioblastomain vitro (AACR 2023) - "MBQ-167 (150 nM-500 nM) also blocked glioblastoma cell migration at 12, 24, and 48 hours. Taken together, these results confirm that MBQ-167 is a viable inhibitor in glioblastoma."

Astrocytoma • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioblastoma • Oncology • Pancreatic Cancer • Solid Tumor • CDC42 • RAC1

Characterization of immunoliposomes for HER2-targeted delivery of the dual Rac/Cdc42 inhibitor MBQ-167 (AACR 2023) - "Even though therapies have been developed to treat this type of breast cancer by targeting HER2 and preventing dimerization (eg. Trastuzumab), patients can present with acquired or intrinsic therapy resistance. Additionally, we determined the excitation/emission parameters (320nm/430nm), quantified a lower limit of detection (LLOD) at 0.1mM, and calculated an encapsulation efficiency of 97% (530μM). Future studies include testing our formulation in vitro and in vivo in HER2+ breast cancer models."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2