bold-100 bold-100 bold-100, or sodium trans-, 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. bold-100 is being developed by bold therapeutics inc. bold-100bold-100 chemical structureclinical dataroutes ofadministrationintravenousidentifiers iupac name sodium trans- cas number197723-00-5pubchem cid9806062drugbank75535930chebichebi:176975chemical and physical data3d model (jsmol)interactive image smiles c1=cc=c2c(=c1)c=nn2.c1=cc=c2c(=c1)c=nn2..cl(cl)(cl)cl inchi inchi=1s/2c7h6n2.4clh.na.ru/c2*1-2-4-7-6(3-1)5-8-9-7;;;;;;/h2*1-5h,(h,8,9);4*1h;;/q;;;;;;+1;+4/p-4key:ygddgjpswmfecs-uhfffaoysa-j 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 bold-100 derivatives bold-100 is sodium trans- with cesium as an intermediate salt form. bold-100 was developed from the closely related ruthenium molecule kp1339 (also known as it-139 or nkp-1339) which is also sodium trans-, but has different manufacturing methods and purity profiles. the names are often used interchangeably. 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, 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 bold-100 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), while also inducing reactive oxygen species (ros), leading to dna damage. bold-100 can synergize with cytotoxic chemotherapies and targeted agents to improve cancer cell death. bold-100 also causes immunogenic cell death in colon cancer organoids. clinical development the precursor molecule to bold-100, 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. 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.