Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist

Abstract

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER + breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f ]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

“…Amcenestrant is in a Phase 2 trial for patients after progression on ET (AMEERA-3: NCT04059484). Camizestrant (AZD9833) promisingly shows no relative resistance with ESR1-MUT Y537S in preclinical models [ 56 ], was effective against endocrine-resistant MBC in Phase 1 testing [ 57 ], and is in a Phase 2 trial for patients after progression on ET (SERENA-2: NCT04214288). Giredestrant (GDC-9545) showed clinical benefit in a Phase 1 study in patients after progression on fulvestrant and CDK4/6i [ 58 ] and is in a Phase 2 trial for patients after progression on ET (acelERA: NCT04576455).…”

Nuclear magnetic resonance free ligand conformations and atomic resolution dynamics

“…Herein, we demonstrate incorporation of molecular dynamics, specifically an efficient version using replica exchange with solute tempering (REST-MD) (Liu et al, 2005;Huang et al, 2007;Wang et al, 2011), into an NMR-based semi-automatic drug discovery platform, to visualize rotational barriers around molecular bonds. Good agreement is demonstrated between REST-MD-calculated energy barriers and NMR measurements, using a small-molecule selective estrogen-receptor degrader (SERD) example from a recent Oncology R&D project (Scott et al, 2016(Scott et al, , 2019(Scott et al, , 2020. The theoretical and experimental data complement each other: REST-MD simplifies the interpretation of NMR conformational dynamics, while the experimental NMR results can inform calculations by defining site-specific preferred torsions of the dominant conformer and experimental conformer distributions, which may influence the initial REST-MD 3D geometry and the sampling ergodicity achieved, as reflected in the resultant histograms.…”

“…The sum of square differences determines the goodness-of-fit between experimental and calculated values to select a best-fit population-weighted model. The fundamental concept of filtering theoretical conformations through experimental data to derive the best fit has become well established over the decades, together with variations in details of implementation, to determine the conformational preference(s) of a small molecule in solution (Cicero et al, 1995;Nevins et al, 1999;Slabber et al, 2016;Wu et al, 2017;Balazs et al, 2019;Farès et al, 2019;Atilaw et al, 2021).…”

“…Design teams need to understand whether a molecule readily adopts its "bioactive" conformation in solution to optimize the binding on-Figure 1. An illustrative medicinal chemistry design-make-test-analyze (DMTA) cycle for drug discovery; the example shown is taken from a recent Oncology R&D project (Scott et al, 2016(Scott et al, , 2019(Scott et al, , 2020. (a) Design: medicinal chemists design drug molecule ideas, using predicted values from computational models to prioritize which virtual molecules to synthesize.…”

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective

“…Compared to acrylic-acid-containing oral SERDs that do not degrade ER equally in different ER+ cell lines, basic SERDs were optimized to deliver maximal ERα degradation across multiple ER+ cell lines, a feature possessed by fulvestrant. This new SERDs has oral and brain bioavailability, while maintaining high-affinity binding to ERα and both potency and efficacy comparable to fulvestrant in ET-resistant or ESR1-mutated cell lines [19,68]. (Figure 3) 3.2.4.…”