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BOLD-100

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BOLD-100
File:BOLD-100.tif
BOLD-100 Chemical Structure
Clinical data
Routes of
administration		Intravenous
Identifiers
  • sodium trans-[Tetrachlorobis(1H-indazole)ruthenate(III)]

BOLD-100, or sodium trans-[tetrachlorobis (1H-indazole)ruthenate(III)], is a ruthenium-based anti-cancer therapeutic in clinical development. As of November 2021, BOLD-100 was being tested in a Phase 1b clinical trial in patients with advanced gastrointestinal cancers in combination with the chemotherapy regimen FOLFOX.[1] BOLD-100 is being developed by Bold Therapeutics Inc.[2]

Structure

BOLD-100 has an octahedral structure with two trans indazoles and four chloride ligands in the equatorial plane. The primary cation for BOLD-100 is sodium. BOLD-100’s impurity profile contains trace quantities of cesium [3].

BOLD-100 derivatives

BOLD-100 was developed from the closely related ruthenium molecule KP1339, also known as IT-139 or NKP-1339. Both BOLD-100 and KP1339 have the same active pharmaceutical ingredient, sodium trans-[tetrachlorobis (1H-indazole) ruthenate(III)], but have different manufacturing methods and purity profiles. The names are often used interchangeably. [4]

The precursor molecule to BOLD-100 is KP1019, which is the indazole salt equivalent. KP1019 previously entered Phase 1 clinical trials but development was halted due to low solubility in water [5], leading to the development of KP1339 and BOLD-100 which are readily soluble in water. KP1019 and KP1339 were invented by Dr. Keppler at the University of Vienna.

Synthesis

Synthesis of the drug substance is accomplished by treating RuCl3 with an excess of 1H-indazole in a concentrated aqueous HCl solution. The resulting indazolium salt is treated with CsCl, and a salt exchange is performed that converts the cesium salt to the final sodium salt. The drug product is prepared as a lyophilized powder for parenteral administration.

Mechanism of action

BOLD-100 kills cancer cells through multiple mechanisms, leading to cell death through apoptosis. BOLD-100 inhibits GRP78 and alters the unfolded protein response (UPR). BOLD-100 induces reactive oxygen species (ROS), leading to DNA damage. [6] BOLD-100 can synergize with cytotoxic chemotherapies and targeted agents to improve cancer cell death [7] BOLD-100 also causes immunogenic cell death in colon cancer organoids [8]

Clinical development

KP1339 was tested in a Phase 1 monotherapy clinical trial in heavily pretreated patients with advanced cancers. In this dose escalation study, KP1339 was administered to 46 patients with doses ranging from 20 mg/m2 to 780 mg/m2. KP1339 was well tolerated, with the treatment-emergent adverse events occurring in >20% of patients being nausea, fatigue, vomiting, anaemia and dehydration. These adverse events were mainly grade 2 or lower. In the 38 efficacy-evaluable patients, nine patients achieved stable disease and 1 patient had a durable partial response. 625 mg/m2 was determined to be the recommended Phase 2 dose [9] BOLD-100 is being tested in a Phase 1b clinical trial in combination with the chemotherapy regimen FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) for the treatment of gastrointestinal cancers, including gastric, pancreatic, colon and bile duct cancer. This trial includes a dose escalation phase followed by a cohort expansion and is expected to enroll 80 patients. [10]

References

  1. ^ U.S. National Library of Medicine. (2020). BOLD-100 in combination with FOLFOX for the treatment of advanced solid tumours. https://clinicaltrials.gov/ct2/show/NCT04421820
  2. ^ Bold Therapeutics. (2021). Technology. https://www.bold-therapeutics.com/technology
  3. ^ Vojkovsky, T., Sill, K., Carie, A. (2018). Manufacture of trans-[tetrachlorobis(1H-inadazole)ruthenate(III)] and compositions thereof (U.S. Patent No. 10, 611,787). U.S. Patent and Trademark Office. https://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.htm&r=2&f=G&l=50&d=PTXT&S1=10,611,787&OS=10,611,787&RS=10,611,787)
  4. ^ Bakewell, S., Conde, I., Fallah, Y., McCoy, M., Jin, L., & Shajahan-Haq, A. N. (2020). Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer. Cancers, 12(9), 2647. MDPI AG. https://www.mdpi.com/2072-6694/12/9/2647
  5. ^ Hartinger, C., Jakupec, M., Zorbas-Seifried, S., Groessl, M., Egger, A., Berger, W., Zorbas, H., Dyson, P. and Keppler, B. (2008), KP1019, A New Redox-Active Anticancer Agent – Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients. Chemistry & Biodiversity, 5: 2140-2155. https://doi.org/10.1002/cbdv.200890195
  6. ^ Bakewell S. J., Rangel D. F., Ha D. P., Sethuraman J., Crouse R., Hadley E., Costich T. L., Zhou X., Nichols P., Lee A. S. Suppression of stress induction of the 78-kilodalton glucose regulated protein (GRP78) in cancer by IT-139, an anti-tumor ruthenium small molecule inhibitor. Oncotarget. 2018; 9: 29698-29714. https://www.oncotarget.com/article/25679/text/
  7. ^ Bakewell S. J., Rangel D. F., Ha D. P., Sethuraman J., Crouse R., Hadley E., Costich T. L., Zhou X., Nichols P., Lee A. S. Suppression of stress induction of the 78-kilodalton glucose regulated protein (GRP78) in cancer by IT-139, an anti-tumor ruthenium small molecule inhibitor. Oncotarget. 2018; 9: 29698-29714. https://www.oncotarget.com/article/25679/text/
  8. ^ Wernitznig,D., Kiakos,K., Del Favero, G., Harrer, N., Machat, H., Osswald, A., Jakupec, M., Wernitznig, A., Sommergruber, W., Keppler, B.(2019). First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro, Metallomics, Volume 11, Issue 6, June 2019, Pages 1044–1048. 10.1039/c9mt00051h
  9. ^ Burris HA, Bakewell S, Bendell JC, et al. Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-inhuman, open-label, dose escalation phase I study with expansion cohort . ESMO Open 2016;1:e000154. doi:10.1136/ esmoopen-2016-000154
  10. ^ U.S. National Library of Medicine. (2020). BOLD-100 in combination with FOLFOX for the treatment of advanced solid tumours. https://clinicaltrials.gov/ct2/show/NCT04421820
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