The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects

Hurchla, Michelle A.; García-Gómez, Antonio; Hornick, Mary C.; Ocio, Enrique M.; Li, A.; Blanco, Juan F.; Collins, Lynne; Kirk, Christopher J.; Piwnica‐Worms, David; Vij, Ravi; Tomasson, Michael H.; Pandiella, Atanasio; Miguel, Jesús F. San; Garayoa, Mercedes; Weilbaecher, Katherine N.

doi:10.1038/leu.2012.183

Cited by 112 publications

(109 citation statements)

References 60 publications

(97 reference statements)

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“…Studies in refractory/relapsed MM show responses to carfilzomib in bortezomib-treated or naive individuals (24,25). Further, cell and animal studies show osteoclast suppression and improvement in bone health with proteasome inhibitors, generating optimism that carfilzomib may secondarily prevent some of the bone-destructive processes common to MM (26). These early results indicate that carfilzomib will enhance the arsenal of effective therapies for treatment of MM, and a large phase III trial is underway (27).…”

Section: Therapeuticsmentioning

confidence: 98%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

111

104

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The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics. IntroductionA new era in myeloma therapy. At the turn of the millennium, targeted molecular therapeutics against hematologic malignancies initiated a shift in our perspective on treatment, prognosis, and survival for patients with some of the most aggressive and fatal neoplasms. Bortezomib (branded and marketed as Velcade by Millennium Pharmaceuticals) entered the armamentarium of new antiproliferative therapies with approval in May 2003 for the hematologic malignancy multiple myeloma (MM), in which B cellderived plasma cells clonally proliferate and produce large quantities of monoclonal antibody. MM can be a devastating disease, with renal failure, blood hyperviscosity, and bone marrow invasion seen clinically. Before 2000, there were few life-prolonging therapies for the disease. Bortezomib blocks the proteolytic activity of the 26S proteasome, a cellular structure whose role in cell metabolism has now been meticulously characterized; indeed, bortezomib is the first agent available for use in humans that inhibits the activity of this system. Bortezomib quickly proved effective in refractory MM (1), and its inclusion in initial MM treatment was superior to the conventional cytotoxic chemotherapy regimen alone (2).During this time thalidomide, an agent that produced deformities in infants of mothers prescribed the drug during pregnancy, further suppressed myeloma plasma cell proliferation when added to the regimen. A decade of careful clinical trials since these first breakthrough observations has revealed that therapeutic combinations including bortezomib with thalidomide or related compounds (collectively called immunomodulatory drugs, or IMiDs) and steroids confer a very favorable prognosis compared with historic therapy, greatly prolonging the median survival time from diagnosis over this period (3). When this therapy is implemented in conjunction with autologous bone marrow stem cell transplant, recent clinical trials show a three-year progression-free survival of 60% and overall survival of 90% for patients eligible for stem cell transplant (4), compared with only 48% three-year relative survival for patients diagnosed in 1999 (5). Multiple clinical trials for this new generation of MM molecular therapies are underway, with median survival projected by some to exceed 10 years in the post-bortezomib...

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Section: Therapeuticsmentioning

confidence: 98%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

111

104

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“…This represents an unprecedented advantage for the treatment of both multiple myeloma and MBD either as single agent (12) or in certain combinations with other antimyeloma drugs (11). Preclinical studies with second-generation proteasome inhibitors carfilzomib and ONX0912, have shown that in addition to their antimyeloma properties (45,46) and similar to bortezomib, they effectively target osteoblast and osteoclast populations to shift the bone microenvironment from a catabolic to an anabolic state (27). Akin to these proteasome inhibitors, herewith, we show that MLN2238 also combines antimyeloma activity with antiresorptive and bone-forming effects on bone.…”

Section: Discussionmentioning

confidence: 99%

“…4D and E), thus underscoring the essential role of the IRE1a component of the UPR in the promotion of osteoblast function by proteasome inhibitors. MLN2238 prevents tumor-associated bone loss besides reducing multiple myeloma tumor burden We next explored whether proosteogenic, antiosteoclastogenic, and antimyeloma in vitro effects of MLN2238 could be translated into a disseminated murine model of human myeloma (27). RPMI8226-luc cells were intravenously injected to NSG mice and myeloma engraftment (as monitored by bioluminescence) occurred after 3 weeks.…”

Section: Mln2238 Activates Tcf4/b-catenin Signaling and The Upr Respomentioning

confidence: 99%

“…Alternatively, PBMCs from patients with myeloma were also used. Assays related to osteoclast formation and function included: RANKL-induced NFkB activation, F-actin ring formation, and CD51/61 (aVb3 integrin) expression (preosteoclasts, 14 days differentiation); resorption capacity (17 days differentiation), and osteoclast formation (21 days differentiation), and were performed as in Hurchla and colleagues (27).…”

Section: Cell Culturesmentioning

confidence: 99%

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Preclinical Activity of the Oral Proteasome Inhibitor MLN9708 in Myeloma Bone Disease

García-Gómez

Quwaider

Canavese

et al. 2014

Clinical Cancer Research

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Purpose: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models.Experimental Design: The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities.Results: Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-kB ligand)-induced NF-kB activation, F-actin ring disruption, and diminished expression of aVb3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma

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“…KMS-12-PE and KMS-12-BM were from JCRB (authenticated there by STR) and JJN-3 from DSMZ (authenticated there by multiplex PCR of minisatellite markers). 5TGM1-luc mouse multiple myeloma cells were kindly provided by Dr. Babatunde O. Oyajobi, University of Texas Health Science Center at San Antonio (San Antonio, TX), where this cell line was discovered and characterized (13)(14)(15)(16). All of the above cells were kept in culture for less than 6 months including expansion for aliquot freezing.…”

Section: Cellsmentioning

confidence: 99%

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

et al. 2016

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Multiple myeloma cells secrete more disulfide bond-rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrowsparing compound, exhibited a submicromolar IC 50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in activesite CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma.

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The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects

Cited by 112 publications

References 60 publications

Emerging therapies targeting the ubiquitin proteasome system in cancer

Emerging therapies targeting the ubiquitin proteasome system in cancer

Preclinical Activity of the Oral Proteasome Inhibitor MLN9708 in Myeloma Bone Disease

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

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