ArticleNature communications2018
Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia.
Article in Nature communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03218683 (A Phase 1/1b/2a, 3-Part, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Ascending Doses of AZD5991 Monotherapy and in Combination With Venetoclax in Subjects With Relapsed or Refractory Haematologic Malignancies), which is not on this map. Cited by 264 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1/1b/2a, 3-Part, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Ascending Doses of AZD5991 Monotherapy and in Combination With Venetoclax in Subjects With Relapsed or Refractory Haematologic Malignancies
Who cites it
264 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumors.Histopathology · 2022Pooled it
- ETV6 Rearrangement Suppresses CDKN1B Transcription by Disrupting an Intragenic Super-enhancer in Acute Lymphoblastic Leukemia.Cancer research · 2026Article
- AI-enabled multi-omics pharmacogenomic modeling guides resistance-aware multitarget optimization of venetoclax therapy in acute myeloid leukemia.NPJ precision oncology · 2026Article
- Drug Resistance in Multiple Myeloma: Tumor-Intrinsic Mechanisms and the Bone Marrow Microenvironment.Cell biochemistry and function · 2026Review
- Genomic Subtype Influences BH3 Mimetic Drug Sensitivity and Synergy with Cytotoxic Chemotherapeutics in T-cell Acute Lymphoblastic Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.Cell death & disease · 2026Article
- Proteasome inhibition enhances lysosome-mediated targeted protein degradation.Cell death & disease · 2026Article
- Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies.Molecules (Basel, Switzerland) · 2026Review
- Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies.Journal of clinical medicine · 2026Review
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia.Molecular oncology · 2026Article
- Saga of MCL1 inhibitors in multiple myeloma.Biochemical pharmacology · 2026Review
- Developing therapeutic strategies to target MCL1 and BCLXL in lethal prostate cancer.iScience · 2025Article
- MIM1 - a selective Mcl-1 protein inhibitor augments the proapoptotic activity of moxifloxacin toward MDA-MB-231 triple-negative breast cancer cells - a preliminary in vitro study.Pharmacological reports : PR · 2025Article
- MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis.Nature communications · 2025Article
- Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.Nature reviews. Clinical oncology · 2025Review
- Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer.Nature communications · 2025Article
- Targeting MCL-1 to Overcome Therapeutic Resistance and Improve Cancer Mortality.Health science reports · 2025Article
- PANoptosis-related gene APAF1 may contribute to the progression of sepsis.Irish journal of medical science · 2025Article
- Co-Targeting BCL-xL with MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.Molecular cancer therapeutics · 2025Article
204 more citing papers are in PubMed but not listed here.
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Authors and funding
34 authors.
Funding
No grant is acknowledged in the PubMed record.
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).
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