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Your search keyword '"Booker, Shon K."' showing total 3 results
Start Over Author "Booker, Shon K." Topic pyridines
3 results on '"Booker, Shon K."'

1. Discovery of a Covalent Inhibitor of KRAS G12C (AMG 510) for the Treatment of Solid Tumors.

Author

Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G, Kopecky DJ, Liu L, Lopez P, Low JD, Ma V, Minatti AE, Nguyen TT, Nishimura N, Pickrell AJ, Reed AB, Shin Y, Siegmund AC, Tamayo NA, Tegley CM, Walton MC, Wang HL, Wurz RP, Xue M, Yang KC, Achanta P, Bartberger MD, Canon J, Hollis LS, McCarter JD, Mohr C, Rex K, Saiki AY, San Miguel T, Volak LP, Wang KH, Whittington DA, Zech SG, Lipford JR, and Cee VJ

Subjects
Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Clinical Trials as Topic, Dogs, Drug Discovery, Humans, Isomerism, Madin Darby Canine Kidney Cells, Mice, Inbred BALB C, Mice, Nude, Mutation, Piperazines chemistry, Piperazines pharmacology, Proto-Oncogene Proteins p21(ras) genetics, Pyridines chemistry, Pyridines pharmacokinetics, Pyridines pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology, Pyrimidinones chemistry, Pyrimidinones pharmacokinetics, Rats, Structure-Activity Relationship, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Piperazines therapeutic use, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Pyridines therapeutic use, Pyrimidines therapeutic use, Pyrimidinones therapeutic use
Abstract

KRAS G12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS G12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS G12C inhibitor currently in phase I clinical trials (NCT03600883).

Published
2020
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2. Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.

Author

Smith AL, D'Angelo ND, Bo YY, Booker SK, Cee VJ, Herberich B, Hong FT, Jackson CL, Lanman BA, Liu L, Nishimura N, Pettus LH, Reed AB, Tadesse S, Tamayo NA, Wurz RP, Yang K, Andrews KL, Whittington DA, McCarter JD, Miguel TS, Zalameda L, Jiang J, Subramanian R, Mullady EL, Caenepeel S, Freeman DJ, Wang L, Zhang N, Wu T, Hughes PE, and Norman MH

Subjects
Animals, Biological Availability, Class I Phosphatidylinositol 3-Kinases physiology, Crystallography, X-Ray, Drug Design, Female, Humans, Indazoles chemical synthesis, Indazoles pharmacokinetics, Indazoles pharmacology, Mice, Mice, Nude, Microsomes, Liver metabolism, Models, Molecular, Piperazines pharmacokinetics, Piperazines pharmacology, Proto-Oncogene Proteins c-akt physiology, Purines chemical synthesis, Purines pharmacokinetics, Purines pharmacology, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyridines pharmacokinetics, Pyridines pharmacology, Pyrimidines chemical synthesis, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Signal Transduction, Structure-Activity Relationship, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Sulfones chemical synthesis, Sulfones pharmacokinetics, Sulfones pharmacology, TOR Serine-Threonine Kinases antagonists & inhibitors, Triazines pharmacokinetics, Triazines pharmacology, Xenograft Model Antitumor Assays, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Piperazines chemical synthesis, Pyridines chemical synthesis, Sulfonamides chemical synthesis, Triazines chemical synthesis
Abstract

A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.

Published
2012
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3. Structure-activity relationships of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: investigations of various 6,5-heterocycles to improve metabolic stability.

Author

Stec MM, Andrews KL, Booker SK, Caenepeel S, Freeman DJ, Jiang J, Liao H, McCarter J, Mullady EL, San Miguel T, Subramanian R, Tamayo N, Wang L, Yang K, Zalameda LP, Zhang N, Hughes PE, and Norman MH

Subjects
Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Cell Line, Tumor, Dogs, Drug Screening Assays, Antitumor, Female, Hepatocytes metabolism, Imidazoles chemical synthesis, Imidazoles pharmacokinetics, Imidazoles pharmacology, Mice, Mice, Nude, Models, Molecular, Neoplasm Transplantation, Oxazoles chemical synthesis, Oxazoles chemistry, Oxazoles pharmacology, Pyridazines chemical synthesis, Pyridazines pharmacokinetics, Pyridazines pharmacology, Pyridines pharmacokinetics, Pyridines pharmacology, Rats, Structure-Activity Relationship, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Thiazoles chemical synthesis, Thiazoles chemistry, Thiazoles pharmacology, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, Phosphoinositide-3 Kinase Inhibitors, Pyridines chemical synthesis, Sulfonamides chemical synthesis, TOR Serine-Threonine Kinases antagonists & inhibitors
Abstract

N-(6-(6-Chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (1) is a potent and efficacious inhibitor of PI3Kα and mTOR in vitro and in vivo. However, in hepatocyte and in vivo metabolism studies, 1 was found to undergo deacetylation on the 2-amino substituent of the benzothiazole. As an approach to reduce or eliminate this metabolic deacetylation, a variety of 6,5-heterocyclic analogues were examined as an alternative to the benzothiazole ring. Imidazopyridazine 10 was found to have similar in vitro potency and in vivo efficacy relative to 1, while only minimal amounts of the corresponding deacetylated metabolite of 10 were observed in hepatocytes.

Published
2011
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