Title: Pharmacokinetics of ixazomib, an orally available proteasome inhibitor drugs in pre-clinical and clinical settings1. Purpose Multiple myeloma (MM) is the second frequent hematologic cancer and it is incurable. With continuous effort, immunomodulatory drugs and proteasome inhibitor (PI) are two ma-jor therapy in terms of MM treatment. Bortezomib is the first proteasome inhibitor approved by FDA as an orphan drug. Despite its good pharmacokinetics and pharmacodynamics pro-files, the inconvenience of administration by intravenous injection and severe adverse reaction on peripheral neuropathy limited its use. Therefore, scientist invent a second-generation PI named carfizomib. The same problem occurred in carfizomib as well. Based on this fact, an orally available PI called ixazomib was introduced by researchers. Similar to bortezomib, ix-azomib has a boronic acid as its pharmacophore. In terms of pharmacokinetic profiles, ixazo-mib however displays substantial differences from bortezomib. A better understanding of pharmacokinetic differences between ixazomib and bortezomib may provide important in-sights into the development of next-generation proteasome inhibitor drugs.2. Research content and MethodContent(1) Preclinical and clinical absorption, distribution, metabolism and excretion parameters of ixazomib;(2) Comparison in pharmacokinetic parameters with bortezomib;(3) The sensitivities of ixazomib in solid cancer cell lines.(4) The significance and prospect of new drug development.Method (1) Primarily review the literature and compare the findings reported in preclinical and clinical studies;(2) Experiments of comparing the sensitivities of ixazomib in solid cancer cell lines.3. Project schedule2018/2/21-2018/3/5 Identify topics, collect relevant information2018/3/5-2018/3/18 Write an opening report and start research2018/3/18-2018/4/9 Collect data, conduct research, form a writing outline, and conduct mid-term inspections2018/4/9-2018/5/1 In-depth study to form the first draft of the paper2018/5/1-2018/5/27 Paper revision, finalization, printing, reply 4. Literature reviewIxazomib is approved in 2015, and bortezomib is considered as the first level drug in MM treatment. There is only a few researches related to ixazomib. The existing research mainly focuses on the following points. (1) Chemical structure and mechanism of ixazomibIxazomib (MLN9708) is a prodrug and it easily metabolized to MLN2238 in body environment when administrated by oral. MLN2238 is the activated form of ixazomib and belongs to the class of dipeptidyl boronate proteasome inhibitors. Its structure includes four moiety: basic skeleton of dipeptide, 1, 4-Dichlorophenyl, the leucine side chain and boronic acid moiety, and the boronic acid moiety is the pharmacophore that reacts to the target.Because both ixazomib and bortezomib share the same pharmacophore, the inhibition mechanism of them is believed to be similar. [3] Once the drugs is metabolized to body, a reversible covalent reaction occur between the pharmacophore of the drug and 20S proteasome. There are three activate sites, chymotrypsin-like proteolytic (beta;5), caspase-like proteolytic (beta;1) and trypsin-like proteolytic (beta;2) in 20S protesome. And the drug shows distinct affinity to these subunits: beta;5 (IC50: 3.4 nmol/L) gt;gt; beta;1(IC50: 31nmol/L gt; beta;2 (IC50: 3,500nmol/L). [3] At a low concentration, MLN2238 is predominantly bound to beta;5 subunit where possesses N-terminal threonine. When the drug approaches to the site, lone pair of Thr1Ogamma; of N-terminal threonine attack the boron atom, resulting in tetravalent formal negative charge boron ions and a form of an electron-rich amino. Then amino donate its electron to one of boronate hydroxyl groups, forming a tight hydrogen bridge. This protein-ligand complex inhibit the bound between proteins to be hydrolyzed and 20S proteasome. As a result, it induces the cell apoptosis. [2] As a next-generation proteasome inhibitor, data from Kupprman et al. investigation displayed at the table shows that ixazomib is superior both in pharmacokinetic and pharmadynamic profile to bortezomib. It is likely to owe to the 1, 4-Dichlorophenyl moiety of ixazomib according to the SAR of dipeptidyl boronate proteasome inhibitors that negative and aromatic pending in this position were essential to improve the activity of inhibitors. [5] However, the dissociation half-life (t1/2/min) for bortezomib is 110min and for ixazomib is 18min. [3] This implies the reaction between proteasome and ixazomib is faster than its between proteasome and bortezomib. Maybe because of the steric effect of phenylalanine residue of bortezomib.(2) Mechanism of anti-tumor of ixazomib In vitro studies showed that MLN2238 induces apoptosis in MM cell lines sensitive and resistant to conventional therapies and in cells from MM patients [6]. Furthermore, ixazomib cytotoxicity was also observed against plasma cells from both bortezomib- and lenalidomide-refractory patients. [6] In mouse MM xenograft models, ixazomib induced significant tumor growth inhibition and prolonged survival compared with control mice. [6] Study on mouse models revealed that ixazomib has activity against MM bone disease, enhancing osteoblast formation and inhibiting osteoclast activity. [7]Mechanism of inhibition is describes as follows,a. Proteasome inhibition causes stabilization and accumulation of ubiquitinated proteins in MM cell lines, which activate apoptosis of MM cells; [6]b. MLN2238 decreased the numbers of VEGFR2- and PECAM-positive cells. These data suggest that besides inducing apoptosis, MLN2238 also inhibit tumor-associated angiogenic activity. [6]c. Increase in cleavage of poly (ADP- ribose) polymerase, a marker of apoptosis; [6]d. Activate caspase-3, caspase-8 and caspase-9; upregulation of signaling pathways such as p53-p21, p53-NOXA-PUMA and E2F; [6]e. Activation of ER stress response proteins and inhibition of NFkB pathway, involved in pro-survival signaling. [6] NFkB inhibition reduces the release of cytokines secreted by bone marrow stream cells, important for growth and survival of MM cells, thus the cytoprotective effects of BM microenvi- ronment on MM cells are disrupted. [7]Finally, microRNA profiling of MM cells showed how ixazomib allows upregulation of the expression of a tumor suppressor gene namely miR33b, with constitutively low expression in MM cells. The overexpression of this gene plays a critical role in the tumor growth inhibition and prolonged survival of mouse xenograft models. [8] Integrating existing researches on ixazomib, the efficacy comparison between ixazomib and bortezomib has been investigated, and ixazomib showed much effective than bortezomib. [10] Some of the pharmacokinetic parameters were determined in deep, such as progress curve analysis of the kinetics of ixazomib. [11] There are also some researches on ixazomib affecting on solid tumor, and in vitro results showed that ixazomib had cytotoxic effects and induced apoptosis. [12-14]But the sensitivities of ixazomib in solid cancer cell lines is remain to be investigated. In spite of a simple review of pharmacokinetic of ixazomib, [15] there is no article combining all the pharmacokinetics of ixazomib. So it is necessary to do a concrete summary of the pharmacokinetic properties of this new drugs to proving a better understanding of pharmacokinetic differences between ixazomib and bortezomib and guiding the discovery of new drugs. This paper will focus on the pharmacokinetic profiles of ixazomib. Starting from the chemical structure of ixazomib and its pharmacophore and how it inhibits the proteasome (mechanism of action) to the activation of ixazomib (conversion from the prodrug to its pharmacological active form; how ixazomib loses citric acid moiety), its major side effects, its oral bioavailability, its major metabolic enzymes and its major metabolites current clinical dosing. Then I will discuss the pharmacokinetic characteristics of ixazomib and do necessary related experiments to form a system profile of ixazomib.5. References [1]Barbara Muz, Rachel Nicole Ghazarian. Spotlight on ixazomib: potential in the treatment of multiple myeloma [J]. Drug Design, Development and Therapy 2016:10 217226.[2]Michael Groll, Celia R.Berkers Crystal Structure of the Boronic Acid-Based Proteasome Inhibitor Bortezomib in Complex with the Yeast 20S Proteasome [J]. Structure, Volume 14, Issue 3, March 2006, Pages 451-456.[3]Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer [J]. Cancer Res. 2010; 70(5):1970-80. [4]Goldberg AL. Development of proteasome inhibitors as research tools and cancer drugs [J]. J Cell Biol. 2012 Nov 12; 199(4):583-8.[5] Yongqiang Zhu, et al. Design, Synthesis, Biological Evaluation, and Structure-Activity Relationship (SAR) Discussion of Dipeptidyl Boronate Proteasome Inhibitors, Part I: Comprehensive Understanding of the SAR of r-Amino Acid Boronates[J]. J. Med. Chem. 2009, 52, 41924199.[6] Dharminder Chauhan, Ze Tian In vitro and In vivo Selective Antitumor Activity of a Novel Orally Bioavailable Proteasome Inhibitor MLN9708 Against Multiple Myeloma Cells [J]. Clin Cancer Res. Author manuscript, 2011 August 15; 17(16): 53115321.[7] Garcia-Gomez A, Quwaider D, Canavese M, et al. Preclinical activity of the oral proteasome inhibitor MLN9708 in myeloma bone disease [J]. Clin Cancer Res 2014; 20:154254.[8] Tian Z, Zhao J-J, Tai Y-T, et al. Investigational agent MLN9708/2238 targets tumor suppressor miR33b in MM cells [J]. Blood 2012; 120:395867.[9] Brian B. Hasinoff.Progress curve analysis of the kinetics of slow-binding anticancer drug inhibitors of the 20S proteasome [J]. Archives of Biochemistry and Biophysics Volume 639, 1 February 2018, Pages 52-58.[10] Selin Engr, Miri Dikmen, Yusuf ztrk. Comparison of antiproliferative and apoptotic effects of a novel proteasome inhibitor MLN2238 with bortezomib on K562 chronic myeloid leukemia cells [J]. Immunopharmacology and Immunotoxicology, 38:2, 87-97.[11] Brian B. Hasinof. Progress curve analysis of the kinetics of slow-binding anticancer drug inhibitors of the 20S proteasome [J]. Archives of Biochemistry and Biophysics 639 (2018) 5258[12] Smith, D. C. et al. Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies [J]. Invest New Drugs. 33, 652663 (2015).[13] Chattopadhyay, N. et al. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism [J]. PloS One 10, e0144825 (2015).[14] HaoWang, et al. Next-generation proteasome inhibitor MLN9708 sensitizes breast cancer cells to doxorubicininduced apoptosis [J]. Scientific Reports | 6:26456 | DOI: 10.1038/srep26456.[15] Marco Salvini, Rossella Troia, Davide Giudice, et al. Pharmacokinetic drug evaluation of ixazomib citrate for the treatment of multiple myeloma [J]. Expert Opinion on Drug Metabolism amp; Toxicology, DOI:10.1080/17425255.2018.1417388.
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