A phase I/II trial of enzalutamide plus the glucocorticoid receptor antagonist mifepristone for patients with metastatic castration-resistant prostate cancer (mCRPC).

Szmulewitz, Russell Z.; Nabhan, Chadi; O’Donnell, Peter H.; Kach, Jacob; Karrison, Theodore; Martinez, Elia; Stadler, Walter M.

doi:10.1200/jco.2016.34.15_suppl.tps5091

Cited by 2 publications

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“…Replacing the 4-dimethylaminophenyl with a constrained substituent 4-pyrrolidinylphenyl (18) did not improve its GR antagonistic potency. Similarly, changing the 4-dimethylaminophenyl to a 4-pyrrolylphenyl (19) provided no improvement in GR antagonism. A bigger change resulting from the replacement of the C11 aniline by a 4methoxylphenyl (20) did not improve the GR potency either.…”

Section: ■ Results and Discussionmentioning

confidence: 96%

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Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633)

Eksterowicz

Zhou

et al. 2019

J. Med. Chem.

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Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 (15) emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to 1. Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.

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Section: ■ Results and Discussionmentioning

confidence: 96%

“…For example, the combinations of 1 with enzalutamide and nab-paclitaxel are being evaluated in castration-resistant prostate cancer (CRPC) and TNBC, respectively. However, 1 exhibits partial AR agonistic activity and potent progesterone receptor (PR) antagonistic activity (IC 50 = 0.4 nM, Figure ).…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633)

Eksterowicz

Zhou

et al. 2019

J. Med. Chem.

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Molecular Recognition of DNA by Py–Im Polyamides: From Discovery to Oncology

Dervan

Kurmis

Finn

2018

DNA-targeting Molecules as Therapeutic Agents

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The development of Py–Im polyamides as potential therapeutic agents is an example of the application of fundamental science at all levels from initial concept, based on purely chemical considerations of DNA–binding, through refinement of the design process to improvements in synthesis, critical analysis of DNA–binding properties, solving problems of cell uptake and distribution, pharmacokinetics and whole–animal studies leading up to clinical trials. This chapter will document the story with particular regard to the development of drugs aimed at treating one of the most prevalent cancers that beset patients today, therapy-resistant prostate cancer.

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A phase I/II trial of enzalutamide plus the glucocorticoid receptor antagonist mifepristone for patients with metastatic castration-resistant prostate cancer (mCRPC).

Cited by 2 publications

References 0 publications

Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633)

Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633)

Molecular Recognition of DNA by Py–Im Polyamides: From Discovery to Oncology

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