{ "comments": "Bortezomib is a dipeptide (Phe-Leu), with a pyrazinoic acid protecting the N-terminus and a boronic acid replacing the C-terminal carboxylic acid. The boron atom is believed to interact with and inactivate the catalytic site on β subunits which form the active core of the proteasome, preferentially binding β5 active site . Bortezomib is the first-in-class proteasome inhibitor to be approved for clinical use.
Proteasome activity is reviewed in .

The compound also has antimalarial activity. The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.", "bioactivityComments": "Bortezomib has been shown to inhibit the chymotrypsin-like (aka β5) activity of the human 26S proteasome .
Specific activity against the P. falciparum β5 subunit has also been demonstrated . The interaction table below provides data from an evaluation of the antimalarial (asexual blood stage) activity of bortezomib, using a panel of P. falciparum strains. The compound shows no evidence of reduced potency against drug resistant strains .", "clinicalUse": "May be used to treat multiple myeloma in patients unsuccessfully treated with at least two previous therapies. Bortezomib is delivered by injection. The marketed drug Velcade, contains bortezomib as the mannitol boronic ester.", "mechanismOfAction": "Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome. Inhibitors of proteasome activity are antiproliferative and pro-apoptotic in nature. Proteasome inhibition leads to an increase in intracellular pro-apoptotic proteins, which promote cell-cycle arrest and cell-death .", "absorptionAndDistribution": "", "metabolism": "Bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes, 3A4, 2D6, 2C19, 2C9, and 1A2. Deboronated metabolites are inactive as 26S proteasome inhibitors.", "elimination": "The pathways of elimination of bortezomib have not been characterized in humans.", "populationPharmacokinetics": "", "organFunctionImpairment": "", "immuno": "Bortezomib inhibits activity of both the constitutive proteasome and the immunoproteasome, primarily through interaction with the β5 subunit of the former and the low-molecular mass polypeptide-7 (LMP7) which replaces β5 in the latter. Some clinical efficacy has been detected in patients with systemic lupus erythematosus and other autoimmune disorders .", "gtmp": "Bortezomib demonstrates nanomaolar activity against P. falciparum, blocking intraerythrocytic development of the parasite prior to DNA synthesis . Clinical advancement of bortezomib has been precluded because of concerns over host-parasite selectivity, although further optimization of this class of compound could provide more selective inhibitors .

Potential Target/Mechanism Of Action: in vitro evolution and whole-genome analysis (IVIEWGA) has identified P. falciparum proteasome subunit beta type-5 as the validated target ." }