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Your search keyword '"Everlof, Gerry"' showing total 3 results
Start Over Author "Everlof, Gerry" Topic antineoplastic agents
3 results on '"Everlof, Gerry"'

1. Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.

Author

Hill MD, Quesnelle C, Tokarski J, Fang H, Fanslau C, Haarhoff Z, Kramer M, Madari S, Wiebesiek A, Morrison J, Simmermacher-Mayer J, Sinz M, Westhouse R, Xie C, Zhao J, Huang L, Sheriff S, Yan C, Marsilio F, Everlof G, Zvyaga T, Lee F, Gavai AV, and Degnan AP

Subjects
Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Carbolines administration & dosage, Carbolines chemistry, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental pathology, Mice, Molecular Structure, Proteins metabolism, Structure-Activity Relationship, Triple Negative Breast Neoplasms pathology, Antineoplastic Agents pharmacology, Carbolines pharmacology, Drug Development, Proteins antagonists & inhibitors, Triple Negative Breast Neoplasms drug therapy
Abstract

We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Published
2021
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2. Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.

Author

Gavai AV, Norris D, Delucca G, Tortolani D, Tokarski JS, Dodd D, O'Malley D, Zhao Y, Quesnelle C, Gill P, Vaccaro W, Huynh T, Ahuja V, Han WC, Mussari C, Harikrishnan L, Kamau M, Poss M, Sheriff S, Yan C, Marsilio F, Menard K, Wen ML, Rampulla R, Wu DR, Li J, Zhang H, Li P, Sun D, Yip H, Traeger SC, Zhang Y, Mathur A, Zhang H, Huang C, Yang Z, Ranasinghe A, Everlof G, Raghavan N, Tye CK, Wee S, Hunt JT, Vite G, Westhouse R, and Lee FY

Subjects
Administration, Oral, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Carbazoles administration & dosage, Carbazoles chemistry, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Dose-Response Relationship, Drug, Humans, Molecular Structure, Phenylalanine administration & dosage, Phenylalanine chemistry, Proline administration & dosage, Proline chemistry, Structure-Activity Relationship, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism, Tryptophan administration & dosage, Tryptophan chemistry, Antineoplastic Agents pharmacology, Carbazoles pharmacology, Drug Discovery, Phenylalanine pharmacology, Proline pharmacology, Tryptophan pharmacology
Abstract

Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1 , a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.

Published
2021
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3. Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.

Author

Hill MD, Fang H, Tokarski J, Fanslau C, Haarhoff Z, Huang C, Kramer M, Menard K, Monereau L, Morrison J, Ranasinghe A, Shields EE, Tye CK, Westhouse R, Everlof G, Sheriff S, Yan C, Marsilio F, Zhang L, Zvyaga T, Lee F, Gavai AV, and Degnan AP

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Carbolines chemical synthesis, Carbolines chemistry, Dose-Response Relationship, Drug, Humans, Mice, Molecular Structure, Multiple Myeloma metabolism, Proteins metabolism, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, Antineoplastic Agents pharmacology, Carbolines pharmacology, Drug Development, Multiple Myeloma diet therapy, Proteins antagonists & inhibitors, Triazoles pharmacology
Abstract

We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Published
2021
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