Dynamics-Based Discovery of Novel, Potent Benzoic Acid Derivatives as Orally Bioavailable Selective Estrogen Receptor Degraders for ERα+ Breast Cancer

Abstract

The estrogen receptor α (ERα) is identified as an effective target for the treatment of ERα+ breast cancer; thus, discovery of novel selective estrogen receptor degraders (SERDs) are developed as an effective method to overcome the resistance of breast cancer. Herein, the hot-spot residues for protein–ligand interaction between SERDs and ERα are analyzed by molecular dynamic simulation technology, focusing on the hot-spot residues for four series of designed and synthesized SERDs. SAR studies revealed that while the acrylic acid moiety of AZD9496 is scaffold hopping into benzoic acid, compound D24 exhibits potent binding affinity with ERα, good degradation efficacy of ERα, and inhibitory effect against the MCF-7 breast cancer cell line. Besides, D24 also displays good antitumor efficacy in the MCF-7 human breast cancer xenograft model in vivo, favorable pharmacokinetic properties, excellent druggability, and good safety property, making D24 as a promising drug candidate of SERD for further evaluation.

Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma

“…To further elucidate the changes in protein–ligand interactions in FGFR4 WT and FGFR4 V550L during the MD simulation, we also calculated the binding energy contributions of each residue. The binding energy might mainly attribute to several critical residues, which was defined as hot-spot residues . As shown in Figure f, the hydrophobic interaction of the FGFR4 WT– BLU-554 and FGFR4 WT– A34 complex was decomposed to Leu473, Lys503, Met524, Val548, Cys552, Ala554, Leu619, and Phe631.…”

“…The MD simulation (100 ns) was carried out using the Desmond module in Schrodinger Maestro 2019. Simulation procedures and parameter settings of the MD simulations were similar to our previous studies. , The ligands and proteins were assigned to the OPLS3 force field, while the protonation states of charged residues were also preprocessed. For example, the His were protonated to HID, and the other Asp, Arg, Glu, and Lys were also prepared to deprotonated states.…”

Ferroptosis-related gene signatures in neuroblastoma associated with prognosis

“…PROM2 is sensitive to insulin-like growth factor I receptor inhibitor linsitinib ( Fernando et al, 2021 ), insulin-like growth factor 1 inhibitor GSK1904529A ( Zeng et al, 2021 ), the estrogen receptors alpha antagonist AZD9496 ( Cani et al, 2021 ), and the dual-acting estrogen action inhibitor SR16157 ( Rausch et al, 2011 ). Among them, linsitinib has been reported to have potent antitumor activity in diffuse midline glioma when combined with modified chimeric antigen receptor T-cells ( de Billy et al, 2021 ); GSK1904529A has also been found to inhibit glioma tumor growth, induce apoptosis, and inhibit migration ( Zhou et al, 2015 ), and AZD9496; and SR16157 are potential drugs for treating breast cancer that are present in the early stages of clinical research ( Zhang et al, 2021 ) ( Rausch et al, 2011 ). GCH1 is sensitive to ribavirin, a synthetic nucleoside analogue with broad antiviral activity ( Jurković et al, 2021 ).…”

Cinnamic acid hybrids as anticancer agents: A mini‐review

“…AZD9496 ( 17 ; ( E )−3‐{2,5‐difluoro‐4‐[(1 R ,3 R )−2‐(2‐fluoro‐2‐methylpropyl)−3‐methyl‐2,3,4,9‐tetrahydro‐1 H ‐carbazol‐1‐yl]phenyl}acrylic acid; IC 50 : 0.76 nM, MTT assay) was highly active against MCF‐7 cells. [ 44 ] In the MCF‐7‐xenografted mice model, AZD9496 (50 mg/kg, oral administration) suppressed ~80% tumor volume, whereas in the HCC1428LTED‐xenografted mice model, AZD9496 ( 17 , 5.0 mg/kg, oral administration) reduced ~90% tumor volume. [ 45 ] The pharmacokinetic studies revealed that AZD9496 had excellent oral bioavailability in rats and dogs ( F %: 63% and 74%, respectively).…”