Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia.
Adriana E TronMatthew A BelmonteAmmar AdamBrian M AquilaLawrence H BoiseElisabetta ChiarparinJustin CidadoKevin J EmbreyEric GanglFrancis D GibbonsGareth Peter GregoryDavid HargreavesJ Adam HendricksJeffrey W JohannesRicky W JohnstoneSteven L KazmirskiJason G KettleMichelle L LambShannon M MatulisAjay K NookaMartin J PackerBo PengPhilip B RawlinsDaniel W RobbinsAlwin G SchullerNancy SuWenzhan YangQing YeXiaolan ZhengJ Paul SecristEdwin A ClarkDavid M WilsonStephen E FawellAlexander W HirdPublished in: Nature communications (2018)
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).
Keyphrases
- acute myeloid leukemia
- multiple myeloma
- oxidative stress
- clinical trial
- cell death
- allogeneic hematopoietic stem cell transplantation
- endoplasmic reticulum stress
- poor prognosis
- small molecule
- randomized controlled trial
- signaling pathway
- open label
- stem cells
- acute lymphoblastic leukemia
- anti inflammatory
- electronic health record
- combination therapy
- deep learning
- newly diagnosed
- quantum dots
- drug induced
- capillary electrophoresis
- childhood cancer