AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia

Yi, Xue; Sarkar, Aloke; Kısmalı, Görkem; Aslan, Burcu; Ayres, Mary; Iles, La Kesla; Keating, Michael J.; Wierda, William G.; Long, James P.; Bertilaccio, Maria Teresa Sabrina; Gandhi, Varsha

doi:10.1158/1078-0432.ccr-19-1397

Cited by 44 publications

(34 citation statements)

References 51 publications

(57 reference statements)

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“…AMG 176 induced CLL cell death via the mitochondrial pathway with an increase of BAX and BAK in the mitochondrial protein fraction, indicating oligomerization of these proteins. Finally, a synergistic effect was observed between venetoclax and AMG-176 [ 121 ].…”

Section: Hematological Malignanciesmentioning

confidence: 99%

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

et al. 2020

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Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.

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Section: Hematological Malignanciesmentioning

confidence: 99%

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

et al. 2020

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“…Given the indisputable role of MCL-1 in pathogenesis of B-NHL (discussed above) and also in resistance of B-NHL to anti-lymphoma agents including venetoclax (see below), MCL-1 represents an attractive therapeutic target. Targeting MCL-1 directly with selective inhibitors, or indirectly with agents that cause downregulation of MCL-1 as part of their mechanism of action, proved to be efficient in numerous preclinical models of B-NHL, including DLBCL, MCL, BL or CLL [105][106][107][108][109]. Interestingly, we and others have shown that combined inhibition of MCL-1 and BCL-2 is highly effective in preclinical models of B-NHL [58,[105][106][107].…”

Section: Selective Inhibitors Of Mcl-1 and Bcl-xl Inhibitors In Chronmentioning

confidence: 89%

BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

Klánová

Klener

2020

Cancers

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The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.

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“…Outstanding progress has been recently made in the discovery of selective and potent MCL-1 BH3 mimetics and several compounds are currently investigated in phase 1 clinical trials in mature B-cell malignancies ( Table 4). Despite the particular chemical features of each compound, they all exhibit a high specificity for MCL-1 and were reported to induce apoptosis in MM, MCL, and CLL pre-clinical studies [66][67][68]. It is notable that the addiction to MCL-1 of primary cells from MM patients at relapse is increased compared to those at diagnosis [57].…”

Section: Bh3 Mimetics Targeting Mcl-1mentioning

confidence: 99%

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Jullien

Gomez‐Bougie

Chiron

et al. 2020

Cells

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Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-X L ) is a common hallmark in cancers. To divert this dysregulation into vulnerability, researchers have developed BH3 mimetics, which are small molecules that restore effective apoptosis in neoplastic cells by interfering with anti-apoptotic proteins. Among them, venetoclax is a potent and selective BCL-2 inhibitor, which has demonstrated the strongest clinical activity in mature B-cell malignancies, including chronic lymphoid leukemia, mantle-cell lymphoma, and multiple myeloma. Nevertheless, mechanisms of primary and acquired resistance have been recently described and several features such as cytogenetic abnormalities, BCL-2 family expression, and ex vivo drug testing have to be considered for predicting sensitivity to BH3 mimetics and helping in the identification of patients able to respond. The medical need to overcome resistance to BH3 mimetics supports the evaluation of innovative combination strategies. Novel agents including MCL-1 targeting BH3 mimetics are currently evaluated and may represent new therapeutic options in the field. The present review summarizes the current knowledge regarding venetoclax and other BH3 mimetics for the treatment of mature B-cell malignancies.

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AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia

Cited by 44 publications

References 51 publications

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

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