Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

Tron, Adriana E.; Belmonte, Matthew A.; Adam, Ammar; Aquila, Brian; Boise, Lawrence H.; Chiarparin, Elisabetta; Cidado, Justin; Embrey, Kevin J.; Gangl, Eric; Gibbons, Francis D.; Gregory, Gareth P.; Hargreaves, David; Hendricks, J. Adam; Johannes, Jeffrey W.; Johnstone, Ricky W.; Kazmirski, Steven L.; Kettle, Jason G.; Lamb, Michelle L.; Matulis, Shannon M.; Nooka, Ajay K.; Packer, Martin J.; Peng, Bo; Rawlins, Philip; Robbins, Daniel W.; Schuller, Alwin G.; Su, Nancy; Yang, Wenzhan; Ye, Qing; Zheng, Xiaolan; Secrist, J. Paul; Clark, Edwin; Wilson, David M.; Fawell, Stephen E.; Hird, Alexander W.

doi:10.1038/s41467-018-07551-w

Cited by 367 publications

(310 citation statements)

References 45 publications

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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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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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“…Thus, many authors evaluate only antitumor activity measuring subcutaneous (SC) tumor size reduction in mouse models [27][28][29][30], which cannot evaluate the relevant drug effect on AML cells anchored in the bone marrow [6]. Other groups complement the SC model assessment with orthotopic or patient-derived PDX models [31][32][33][34][35][36]; however, the lack of luciferase expression in most models prevents the direct measurement of the drug effect on AML cells affecting the bone marrow, liver, or spleen [10].…”

Section: Discussionmentioning

confidence: 99%

An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

et al. 2020

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Background: Current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival. Methods:Monomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli. Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice (n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups.Results: T22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model.(Continued on next page)

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“…The observation that MCL1 is frequently amplified in human cancers has driven significant efforts to develop potent and specific MCL-1 inhibitors (9). Indeed, several candidate MCL-1 inhibitors have shown on-target efficacy when tested in human hematological malignancies in culture and xenograft models (17)(18)(19)45). The concept that perturbations of the heme synthesis pathway can affect apoptotic responses has precedent.…”

Section: Discussionmentioning

confidence: 99%

“…There has been notable progress in the clinical development of specific and potent MCL-1 inhibitors (e.g. S63845, AMG397, AMG176, and AZD5991); however, none are currently FDA approved, and the FDA recently placed a clinical hold on a phase I, dose escalation study of AMG397 after preliminary findings suggested some cardiac toxicity in patients (17)(18)(19). While the extent of the cardiac toxicity is still being evaluated, genetic deletion of Mcl1 in adult mouse cardiomyocytes also triggered a rapid, fatal cardiomyopathy (20,21).…”

Section: Introductionmentioning

confidence: 99%

Heme-Sensing Pathway Modulates Susceptibility of Poor Prognosis B-Lineage Acute Leukemia to BH3-Mimetics

Smith

Budhraja

Lynch

et al. 2020

Preprint

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211 Words Body: 5960 Words (not counting references nor supplementary material) Heme-sensing pathway dictates apoptotic response 2 Abstract:Anti-apoptotic MCL1 is one of the most frequently amplified genes in human cancers and elevated expression confers resistance to many therapeutics including the BH3-mimetic agents dihydroartemisinin (DHA) translationally represses MCL-1 and synergizes with BH3-mimetics. To explore how DHA represses MCL-1, a genome-wide CRISPR screen identified that loss of genes in the heme synthesis pathway renders mouse BCR-ABL + B-ALL cells resistant to DHAinduced death. Mechanistically, DHA disrupts the interaction between heme and the eIF2α kinase heme regulated inhibitor (HRI) triggering the integrated stress response. Genetic ablation ofEif2ak1, which encodes HRI, blocks MCL-1 repression in response to DHA treatment and represses the synergistic killing of DHA and BH3-mimetics compared to wild-type leukemia. Furthermore, BTdCPU, a small-molecule activator of HRI, similarly triggers MCL-1 repression and synergizes with BH3-mimetics in mouse and human leukemia including both Ph + and Ph-like B-ALL. Lastly, combinatorial treatment of leukemia bearing mice with both BTdCPU and a BH3-mimetic extended survival and repressed MCL-1 in vivo. These findings reveal for the first time that the HRI-dependent cellular heme-sensing pathway can modulate apoptosis in leukemic cells by repressing MCL-1 and increasing their responsiveness to BH3-mimetics. This signaling pathway could represent a generalizable mechanism for repressing MCL-1 expression in malignant cells and sensitizing them to available therapeutics. Heme-sensing pathway dictates apoptotic response Heme-sensing pathway dictates apoptotic response 6 Materials and Methods Cells and Cell Culture. Mouse p185 + Arf-null B-ALL (hereafter referred to as BCR-ABL + B-ALL) (10) and PAX5-JAK2, RCSD1-AB1, and RCSD1-ABL2 fusion-expressing Ph-like Ba/F3 cells (23) were grown in RPMI with 10% fetal bovine serum, 55 µM 2mercaptoethanol, 2 mM glutamine, penicillin, and streptomycin (Invitrogen). Navitoclax and Venetoclax were obtained from Selleckchem. DHA was obtained from AvaChem Scientific. BTdCPU was obtained from Millipore and synthesized by the The human Ph + leukemia cell lines OP-1, TOM-1, BV-173, and SUP-B15 were cultured in RPMI with 20% fetal bovine serum, 55 µM 2-mercaptoethanol, 2 mM glutamine, penicillin, and streptomycin. Genome-wide CRISPR Screen. Cas9-expressing p185 + B-ALL cells were transduced with the Brie CRISPR KO library (Addgene #73633) at a multiplicity of infection of 0.5with an sgRNA coverage of 400x (24). One day after transduction, puromycin was added (1 µg/mL) to select for infected cells. Cells were then cultured in either DMSO or 10 µM DHA containing media for 24 hours (h), followed by a 48h culture in drug free media.As previously described, genomic DNA was extracted from the surviving cells (Qiagen DNeasy Blood and Tissue kit) and amplified by PCR for Illumina sequencing of sgRNAs by Nextseq (24). MAGeCK was used to ...

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Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

Cited by 367 publications

References 45 publications

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

Heme-Sensing Pathway Modulates Susceptibility of Poor Prognosis B-Lineage Acute Leukemia to BH3-Mimetics

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