MBQ-167 efficacy

MBQ-167 targets the GTPases Rac1 and Cdc42 simultaneously. Rac1 and CDC42 are novel therapeutic targets which control the activity of the cancer cell skeleton, a critical functional element connected to the process of metastasis and tumor cell growth. MBQ-167 is a first-in-class, selective GTPase inhibitor which has been shown to prevent metastasis and remove pre-existing metastases for breast cancer tumors in various mouse models.

MBQ-167 safety

Preclinical development of MBQ-167 revealed an excellent safety profile and good bioavailability and pharmacokinetics. Based on these encouraging data for an excellent safety profile, the USFDA accepted in June 2022 the Investigational New Drug (IND) for a Phase 1 Open-Label, First-in-Human Trial of Oral MBQ-167 as Single Agent in Subjects with Advanced Breast Cancer.

MBQ-167 is a first-in-class dual Rac and Cdc42 activation inhibitor

Rac and CDC42 activation curves for MBQ-167 show efficient binding of MBQ-167 to the phosphosrylation sites in Rac and CDC42.

MBQ-167 monotherapy inhibits breast cancer metastasis

MBQ-167 not only reduces primary tumor growth rates, but also prevents metastasis. The experiment below demonstrates both reduction in tumor growth rates for two different cancer cell lines as well as prevention of metastases. MBQ-167 inhibits intravasation (spread of breast cancer from breast tumors (human breast cancer cells tagged with green fluorescent protein) to distant organs and extravasation (direct colonization of distant organs, such as the lung).

Experimental Design

Day 0:
Inoculate GFP-tagged MDA-MB-435 or MDA-MB-231 cells into mammary fat pads in SCID mice

Day 7:
Administer MBQ-167 intraperitoneally when the tumor size reaches about 100 mm3

Day 60:
Image tumor fluorescence

MBQ-167 synergizes with paclitaxel to remove established metastases

In addition to reduction in primary tumor growth rates and prevention of metastases, MBQ-167 together with a standard of care such as paclitaxel removes pre-existing metastases. This can be shown with a study design such as the one in the experiment below. A key step in this experiment is the removal of the primary 4T1 cell tumors before treatment, to make sure that the combined MBQ-167/Paclitaxel therapy removes pre-existing metastases, independently of MBQ-167 inhibition of primary tumor growth.

Experimental Design

Day 0
Establish 4T1 cell tumors

Day 14
Excise primary tumors

Day 21
Image lungs and quantify metastasis base level

Day 21 – Day 38
Oral treatment with MBQ-167 5 times a week

Day 38
Image and excise lungs and quantify metastasis

MBQ-167 monotherapy inhibits breast cancer tumor growth

MBQ-167 inhibits > 90% tumor growth in MDA-MB-435, a human trastuzumab-resistant tumor cell mouse model and in MDA-MB-231, a human TNBC tumor cell mouse model.

MBQ-167 suppresses pancreatic cancer cell growth

MBQ-167 inhibits cancer cell growth. It also inhibits (not shown) cancer cell growth throughout the NCI-60 cancer cell panel.

No MBQ-167-dependent toxicity in standard IND nonclinical safety assessment package

MBQ-167 nonclinical safety was evaluated throughout the UPR R&D period of 2010-2017 and the MBQ Pharma MBQ-167 nonclinical development from 2018-2022. The MBQ-167 GLP nonclinical safety and safety pharmacology assessment packages show a NOAEL in rats and dogs of 1,000 mg/kg/day, and no MBQ-167-dependent findings in the FDA-required tests. The therapeutic dose window for MBQ-167 in these animal models is quite broad, with a minimum therapeutic dose of approximately 100 mg/kg/day.

2010 – 2017 2018 – 2021
Initial in vitro and in vivo studies as part of sponsored academic research projects: No findings
  • Ames Test: Negative
  • In vivo Micronucleus Assay: Negative
  • Non-GLP rat dose escalation and repeat dose studies: Negative whole animal, pathology reports and phagocytosis assay. (NOAEL = 1,000 mg/kg)
  • Non-GLP dog dose escalation studies: Negative whole animal and pathology reports (NOAEL = 1,000 mg/kg)
  • GLP 28-day rat and dog repeat dose studies: Negative whole animal and pathology reports
  • GLP Respiratory, CNS, Cardiovascular, hERG safety pharmacology studies: Negative
  • In vitro 3T3 neutral red uptake phototoxicity assay: Positive (avoid sun exposure)

2010 – 2017:

Initial in vitro and in vivo studies as part of sponsored academic research projects: No findings

2018 – 2021:

  • Ames Test: Negative
  • In vivo Micronucleus Assay: Negative
  • Non-GLP rat dose escalation and repeat dose studies: Negative whole animal, pathology reports and phagocytosis assay. (NOAEL = 1,000 mg/kg)
  • Non-GLP dog dose escalation studies: Negative whole animal and pathology reports (NOAEL = 1,000 mg/kg)
  • GLP 28-day rat and dog repeat dose studies: Negative whole animal and pathology reports
  • GLP Respiratory, CNS, Cardiovascular, hERG safety pharmacology studies: Negative
  • In vitro 3T3 neutral red uptake phototoxicity assay: Positive (avoid sun exposure)

Patents under License or Assigned to MBQ Pharma

References

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