Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.
Zoltan SzlavikMarton CsekeiAttila PaczalZoltan B SzaboSzabolcs SiposGabor RadicsAgnes ProszenyakBalazs BalintJames B MurrayJames DavidsonI-Jen ChenPawel DokurnoAllan E SurgenorZoe Marie DanielsRoderick E HubbardGaëtane Le Toumelin-BraizatAudrey ClaperonGaëlle Lysiak-AuvityAnne-Marie GirardAlain BrunoMaia ChanrionFrédéric CollandAna-Leticia MaragnoDidier DemarlesOlivier GenesteAndrás KotschyPublished in: Journal of medicinal chemistry (2020)
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
Keyphrases
- small molecule
- cell therapy
- clinical trial
- cancer therapy
- single cell
- acute myeloid leukemia
- bone marrow
- endothelial cells
- high throughput
- randomized controlled trial
- dendritic cells
- stem cells
- cell proliferation
- squamous cell carcinoma
- papillary thyroid
- drug delivery
- poor prognosis
- immune response
- capillary electrophoresis
- childhood cancer