Dual mechanism estrogen receptor inhibitors

Min, Jian; Nwachukwu, J.C.; Srinivasan, Sathish; Rangarajan, Erumbi S.; Nettles, Charles C.; Guillen, Valeria Sanabria; Ziegler, Yvonne; Yan, Shunchao; Carlson, Kathryn E.; Hou, Yingwei; Kim, Sung Hoon; Novick, Scott J.; Pascal, Bruce D.; Griffin, Patrick R.; Izard, Tina; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.; Nettles, K.W.

doi:10.1101/2020.07.06.189977

Cited by 3 publications

(4 citation statements)

References 73 publications

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“…Interestingly, compound 29 with the dimethylamine group retained high inhibitory activities, but 30 with the isobutyl group was poor in p-ERK inhibition. IC 50 increased to single-and double-digit nanomolars when the 1-position of cyclopropane was derivatized with methyl (32), fluorine atom (33), carbonitrile (37), and ethyl ether (38) (Figure 3G). Introducing the 2-and 3-positions of the cyclopropyl group (34, 35, 36, and 39) was also unfavorable (Figure 3H).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…HRMS (ESI) calcd for C 28 H 30 F 3 N 5 O 2 Na [M + Na] + , 548.2249; found 548.2146. -1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino [3,2-g]quinazolin-3(4H)-yl)(1-fluorocyclopropyl)methanone (33). White solid (mp 136∼137 °C), [α] 20 D 25 (c 1.0, methanol) = +17.8, 29% yield, HPLC purity is >95%; 1 H NMR (600 MHz, acetone-d 6 ) δ 7.68 (t, J = 7.8 Hz, 1H), 7.58 (s,2H),7.47 (t,J = 7.4 Hz,1H),1H),7.06 (d,J = 54.8 Hz,1H),6.94 (s,1H),5.88 (t,J = 6.8 Hz,1H),3H),4.10 (dd,J = 10.9,8.9 Hz,1H),1H),3.23 (s,1H),3.19 (s,2H),2.80 (t,J = 12.1 Hz,1H),2.33 (s,3H),1.62 (d,J = 7.1 Hz,3H),4H).…”

Section: -((S)-11-(((r)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)am...mentioning

confidence: 99%

“…Pharmacokinetic investigations were conducted on male ICR mice. 33 The compounds were dissolved in a mixture containing water, PEG, Tween 80, and DMSO (68:25:2:5). The solution of compound was administered orally at 20 mg/kg.…”

Section: ■ Associated Contentmentioning

confidence: 99%

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Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma

Zhang

Chen

et al. 2022

J. Med. Chem.

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KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many refractory cancers. Son of sevenless homolog 1 (SOS1) is a key regulator of KRAS to modulate KRAS from inactive to active states. Herein, we disclosed efficacy-improving tetra-cyclic quinazoline derivatives as an enhanced scaffold for inhibiting the SOS1–KRAS interaction. Compound 37, which conjugated 1-carbonitrile-cyclopropane to tetra-cyclic quinazoline, showed a twofold higher oral drug exposure and 2.5-fold longer half-life than BI-3406 in CD-1 mouse plasma. In a Mia-paca-2 xenograft model, 37 administrated alone inhibited tumor growth by 71%. Preclinical investigations demonstrated that 37 had a limited inhibition of CYP and hERG. Overall, our studies showed that 37 was a promising drug candidate for treatment of KRAS-driven cancer.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: -((S)-11-(((r)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)am...mentioning

confidence: 99%

See 1 more Smart Citation

Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma

Zhang

Chen

et al. 2022

J. Med. Chem.

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“…The active state positioning of H12 allows coactivator proteins to be recruited to the LBD [23][24][25]. Conversely, repositioning or destabilization of H12 is associated with inactive states of receptors such as an apo state or an antagonist-bound state [18,26]. However, experimental evidence indicates that NRs exist as a dynamic ensemble of conformations whose populations can be modulated by ligand binding or other perturbations [27].…”

Section: Introductionmentioning

confidence: 99%

Ligand-induced shifts in conformational ensembles that describe transcriptional activation

Khan

Braet

Koehler

et al. 2022

eLife

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Nuclear receptors function as ligand-regulated transcription factors whose ability to regulate diverse physiological processes is closely linked with conformational changes induced upon ligand binding. Understanding how conformational populations of nuclear receptors are shifted by various ligands could illuminate strategies for the design of synthetic modulators to regulate specific transcriptional programs. Here, we investigate ligand-induced conformational changes using a reconstructed, ancestral nuclear receptor. By making substitutions at a key position, we engineer receptor variants with altered ligand specificities. We combine cellular and biophysical experiments to characterize transcriptional activity, as well as elucidate mechanisms underlying altered transcription in receptor variants. We then use atomistic molecular dynamics (MD) simulations with enhanced sampling to generate ensembles of wildtype and engineered receptors in combination with multiple ligands, followed by conformational analysis and correlation of MD-based predictions with functional ligand profiles. We determine that conformational ensembles accurately describe ligand responses based on observed population shifts. These studies provide a platform which will allow structural characterization of physiologically-relevant conformational ensembles, as well as provide the ability to design and predict transcriptional responses in novel ligands.

show abstract

Ligand-induced shifts in conformational ensembles that predict transcriptional activation

Khan

Braet

Koehler

et al. 2022

Preprint

View full text Add to dashboard Cite

Nuclear receptors function as ligand-regulated transcription factors whose ability to regulate diverse physiological processes is closely linked with conformational changes induced upon ligand binding. Understanding how conformational populations of nuclear receptors are shifted by various ligands could illuminate strategies for the design of synthetic modulators to regulate specific transcriptional programs. Here, we investigate ligand-induced conformational changes using a reconstructed, ancestral nuclear receptor. By making substitutions at a key position, we engineer receptor variants with altered ligand specificities. We use atomistic molecular dynamics (MD) simulations with enhanced sampling to generate ensembles of wildtype and engineered receptors in combination with multiple ligands, followed by conformational analysis and prediction of ligand activity. We combine cellular and biophysical experiments to allow correlation of MD-based predictions with functional ligand profiles, as well as elucidation of mechanisms underlying altered transcription in receptor variants. We determine that conformational ensembles accurately predict ligand responses based on observed population shifts, even within engineered receptors that were constitutively active or transcriptionally unresponsive in experiments. These studies provide a platform which will allow structural characterization of physiologically-relevant conformational ensembles, as well as provide the ability to design and predict transcriptional responses in novel ligands.

show abstract

Dual mechanism estrogen receptor inhibitors

Cited by 3 publications

References 73 publications

Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma

Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma

Ligand-induced shifts in conformational ensembles that describe transcriptional activation

Ligand-induced shifts in conformational ensembles that predict transcriptional activation

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