MLN2238

MLN2238 is a potent reversible inhibitor that inhibits specific β5 site of the 20S proteasome with IC50 value of 3.4 nM and Ki value of 0.93 nM.[1]    
MLN2238, an N-capped dipeptidyl leucine boronic acid , preferentially bound to and inhibited the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki value of 0.93 nM). As the concentration increased, it also inhibited the caspase-like (β1) with IC50 value of 31 nM and trypsin-like (β2) proteolytic sites with IC50 value of 3,500 nM. The clinical studies in the model of both solid-tumor and hematological xenograft have demonstrated preclinical antitumor activity. Comparing to bortezomib, MLN2238 showed the activity in pharmacokinetics, pharmacodynamics and antitumor. It is believed that the activation of caspases, the p53 pathway, and endoplasmic reticulum stress and inhibition of NF-κB are related to MLN2238-induced MM cell death. [1,2]        
MLN2238 inhibited growth and triggers apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal cells [2]. MLN2238 has significant cytotoxic activity in RSCL and RRCL preclinical models. Although BTZ and MLN2238 have similar reversible proteasome inhibition, the proteasome dissociation half-life (t1/2) of MLN2238 was found to be approximately sixfold faster than BTZ (t1/2 of 18 vs. 110min, respectively) while has the similar LD50 values to BTZ in a variety of cultured mammalian cancer cell lines. MLN2238 is approximately two to three times more potent than BTZ in lymphoma cell models. The IC50 of MLN2238 was 2.5 nmol/l in contrast to 7.5nmol/l of BTZ in Raji parental cells. [3]
In many mouse models of hematologic malignancies, such as tumor xenograft models which derived from a human lymphoma cell line and primary human lymphoma tissue, and genetically engineered mouse models of plasma cell malignancies, the result showed the antitumor activity of MLN2238.[4]
References:
1.Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Research, 2010, 70 (5): 1970-80.
2.Tian Z, Zhao J, Tai Y, et al. Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells. Blood, 2012, 120 (19): 3958-3967
3.Gu JJ,  Hernandez-Ilizaliturri FJ, Mavis C, et al. MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models. ANTI-CANCER DRUGS, 2013, 24 (10): 1030-1038.
4.Lee EC, Fitzgerald M, Bannerman B, et al. Antitumor Activity of the Investigational Proteasome Inhibitor MLN9708 in Mouse Models of B-cell and Plasma Cell Malignancies. CLINICAL CANCER RESEARCH, 2011, 17 (23): 7313-7323.

The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cells in vitro, as a single agent and in combination with other drugs.[Pubmed:24467634]

Br J Haematol. 2014 Apr;165(1):78-88.

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in the U.S. The course of the disease has been shown to be negatively impacted by increased levels of BCL2. Strategies to downregulate BCL2 and shift the balance towards cellular demise are actively being explored. Therefore, we examined whether the investigational agent MLN2238 could inhibit the proteasomal machinery and induce CLL cell death while also downregulating BCL2. MLN2238-induced cell death was studied in peripheral blood mononuclear cells from 28 CLL patients. MLN2238 produced a dose-dependent reduction in BCL2 and CLL cell viability with maximum cell death observed at a 50 nmol/l concentration by 48 h. Annexin-V staining, PARP1 and caspase-3 cleavage along with an increase in mitochondrial membrane permeability were noted after cells were treated with MLN2238; however, apoptosis was only partially blocked by the pan-caspase inhibitor z-VAD.fmk. Furthermore, we observed enhanced anti-CLL effects in tumour cells treated with either a combination of MLN2238 and the BH3 mimetic AT-101 or MLN2238 and fludarabine. Together, our data suggest the potential for proteasome inhibitor based therapy in CLL and the rationale design of drug combination strategies based on CLL biology.

The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma.[Pubmed:27783987]

Oncotarget. 2016 Dec 6;7(49):81172-81186.

The ubiquitin-proteasome signaling pathway is critical for cell cycle regulation and neoplastic growth. Proteasome inhibition can activate apoptotic pathways. Bortezomib, a selective proteasome inhibitor, has anti-melanoma activity. MLN2238 (ixazomib), an oral proteasome inhibitor, has improved pharmacotherapeutic parameters compared to bortezomib. Interferon-alpha (IFN-alpha), an immune boosting agent, is FDA-approved for treatment of melanoma. In this study in vitro and in vivo evaluation of the antitumor potential of ixazomib and combination treatments with ixazomib and IFN-alpha were performed. Apoptosis induced by ixazomib was first observed at 12 hours and was maximal at 48 hours with similar levels of cell death compared to bortezomib. IFN-alpha alone had little effect on cell viability in vitro. However, the combination of ixazomib with IFN-alpha significantly enhanced ixazomib's ability to induce apoptotic cell death in BRAF V600E mutant and BRAF wild-type human melanoma tumor cells. The combination of ixazomib and IFN-alpha also enhanced inhibition of cell proliferation in BRAF V600E mutant melanoma tumor cells; however, this was not seen in BRAF wild-type cells. Ixazomib-induced apoptosis was associated with processing of the pro-apoptotic proteins procaspase-3, -7, -8, and -9, and cleavage of poly-ADP-ribose polymerase (PARP). In an in vivo xenograft model of human melanoma, combination treatment with IFN-alpha-2b and ixazomib demonstrated a significant reduction in tumor volume when compared to vehicle (p = 0.005) and single therapy ixazomib (p = 0.017) and IFN-alpha-2b (p = 0.036). These pre-clinical results support further evaluation of combination treatment with ixazomib and IFN-alpha for the treatment of advanced BRAF V600E mutant melanoma.

MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA.[Pubmed:25027405]

Tumour Biol. 2014 Oct;35(10):10213-21.

Patients undergoing androgen blockade therapy develop castration-resistant prostate cancer (CRPC), which is associated with Bcl-2 upregulation and results in disease progression and death. In recent years, promising therapeutic agents, such as the BH3-only mimetic ABT-263 and proteasome inhibitors, have been developed and widely evaluated against a broad spectrum of cancer types, including prostate cancer, alone or in combination with other chemotherapeutic agents. In this study, the antitumor efficacy of ABT-263 and MLN2238 were evaluated as single agents and in combination in four CRPC cell lines: PC3, C4-2B, C4-2, and DU145. The viability of the treated cells and markers of apoptosis were assayed. Protein-protein interactions were analyzed by co-immunoprecipitation in drug-treated cells. Lentivirus-mediated short hairpin RNA was used to knockdown Bax, Mcl-1, and NOXA expressions. We found that ABT-263 and MLN2238 alone exhibited a mild cytotoxicity, and in combination, they elicited a synergistic cytotoxic effect in CRPC cells. The cell apoptosis induced by the combination drug treatment was evidenced by enhanced caspase-3 and Poly (ADP-ribose) polymerase (PARP) cleavage, and annexin-V-positive staining was significantly depleted by Bax knockdown. MLN2238 treatment upregulated NOXA and Mcl-1 expression, leading NOXA/Mcl-1 complexes to disassociate Bak from its complexes with Mcl-1 and enhancing ABT263-triggered Bax activation. NOXA knockdown by short hairpin RNA significantly attenuated the cytotoxicity of ABT-263 and MLN2238 co-administration. In conclusion, MLN2238 and ABT-263 synergistically triggered apoptosis in CRPC cells by upregulating NOXA and activating Bax, indicating a promising therapeutic strategy for the treatment of CRPC.

Comparison of antiproliferative and apoptotic effects of a novel proteasome inhibitor MLN2238 with bortezomib on K562 chronic myeloid leukemia cells.[Pubmed:26667773]

Immunopharmacol Immunotoxicol. 2016;38(2):87-97.

Inhibition of the proteasome has emerged as a clinically effective anticancer therapeutic approach in recent years. Bortezomib (Velcade(R)) showed extremely high potency against a wide range of cancer cell lines. Ixazomib (MLN9708-MLN2238), the second-generation proteasome inhibitor, selectivity and potency were similar to that of bortezomib, is currently being investigated in phase I studies. It shows superior antitumor activity in hematologic malignancy, especially multiple myelomas. In this study, for the first time, we evaluated and compared the antiproliferative and apoptotic effects of the novel proteasome inhibitor MLN2238 (the active form of MLN9708) with bortezomib using in vitro chronic myeloid leukemia. Cytotoxic and apoptotic effects of MLN2238 and bortezomib were determined by trypan blue dye exclusion assays, WST-1 cell proliferation assay, increased AnnexinV-PI binding capacity, changes in caspase-3 activity and loss of mitochondrial membrane potential (JC-1). Associated with proteasome pathway NFkappaB1 and c-myc mRNA expression levels were examined by the qRT-PCR method. We observed that cytotoxic and apoptotic effects on K562 cells were started at 5 mum of MLN2238 and 1 mum of bortezomib after 24 and 48 h. Also, MLN2238 and bortezomib downregulated NFkappaB1 and c-myc mRNA expression at 24 h. Our result revealed that MLN22238 and bortezomib had significant cytotoxic and apoptotic effects on K562 cells. Here, we first demonstrate in vitro data that support the development of MLN2238, by direct comparison with bortezomib on K562 cells.

Ixazomib (MLN2238) is a selective, potent, and reversible proteasome inhibitor, which inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 of 3.4 nM (Ki of 0.93 nM).

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