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

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Abstract

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).

Abstract

High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

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Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

William Wierda, John F Gerecitano, Gary Gordon … (2017)

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

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MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program.

Shimin Hu, Zijun Xu-Monette, Alexander Tzankov … (2013)

Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP.

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Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

J D Leverson, H. Zhang, J J Chen … (2015)

The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein–protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1–BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.

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Author and article information

Contributors

Alexander W. Hird:

ORCID: http://orcid.org/0000-0002-2699-7449

alexander.hird@astrazeneca.com

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 17 December 2018

Publication date PMC-release: 17 December 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 5341

Affiliations

[1 ]GRID grid.418152.b, Oncology, IMED Biotech Unit, , AstraZeneca, ; Waltham, MA 02451 USA

[2 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Hematology and Medical Oncology, , Emory University School of Medicine, ; Atlanta, GA 30322 USA

[3 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Winship Cancer Institute of Emory University, ; Atlanta, GA 30322 USA

[4 ]ISNI 0000 0004 5929 4381, GRID grid.417815.e, Oncology, IMED Biotech Unit, , AstraZeneca, ; Cambridge, CB4 0WG UK

[5 ]ISNI 0000 0004 5929 4381, GRID grid.417815.e, Discovery Sciences, IMED Biotech Unit, , AstraZeneca, ; Cambridge, CB4 0WG UK

[6 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, School of Clinical Sciences at Monash Health, , Monash University, ; Clayton, VIC 3800 Australia

[7 ]ISNI 0000000403978434, GRID grid.1055.1, Peter MacCallum Cancer Centre, ; Melbourne, VIC 3000 Australia

[8 ]GRID grid.418152.b, Discovery Sciences, IMED Biotech Unit, , AstraZeneca, ; Waltham, MA 02451 USA

[9 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, The Sir Peter MacCallum Center, Department of Oncology, , University of Melbourne, ; Parkville, VIC 3000 Australia

[10 ]ISNI 0000 0004 5929 4381, GRID grid.417815.e, Oncology, IMED Biotech Unit, , AstraZeneca, ; Alderley Park, SK10 4TG UK

[11 ]GRID grid.418152.b, Pharmaceutical Sciences, IMED Biotech Unit, , AstraZeneca, ; Waltham, MA 02451 USA

[12 ]Present Address: LifeMine Therapeutics, Cambridge, MA USA

[13 ]Present Address: Surface Oncology, Cambridge, MA USA

[14 ]GRID grid.422303.4, Present Address: Alkermes, Inc., ; Waltham, MA USA

[15 ]Present Address: Fulcrum Therapeutics, Cambridge, MA USA

[16 ]Present Address: Nurix, Inc., San Francisco, CA USA

Author information

Gareth P. Gregory http://orcid.org/0000-0002-4170-0682

Jeffrey W. Johannes http://orcid.org/0000-0001-7242-6682

Michelle L. Lamb http://orcid.org/0000-0002-3005-8065

Wenzhan Yang http://orcid.org/0000-0002-4591-5007

Alexander W. Hird http://orcid.org/0000-0002-2699-7449

Article

Publisher ID: 7551

DOI: 10.1038/s41467-018-07551-w

PMC ID: 6297231

PubMed ID: 30559424

SO-VID: f0e72f5c-6c60-4b17-9bbd-af6d38d2474f

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 15 May 2018

Date accepted : 9 November 2018

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

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Most cited references 32

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program.

Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

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