التفاصيل البيبلوغرافية
| العنوان: |
Discovery of 5‑{4-[(7-Ethyl-6-oxo‑5,6-dihydro‑1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}‑ N ‑methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs |
| المؤلفون: |
Jeffrey W. Johannes (1414039), Amber Balazs (9436515), Derek Barratt (8921054), Michal Bista (160356), Matthew D. Chuba (11486389), Sabina Cosulich (466728), Susan E. Critchlow (1613527), Sébastien L. Degorce (1436623), Paolo Di Fruscia (3748813), Scott D. Edmondson (1416967), Kevin Embrey (1637887), Stephen Fawell (5867138), Avipsa Ghosh (1329021), Sonja J. Gill (11486392), Anders Gunnarsson (1454497), Sudhir M. Hande (2047519), Tom D. Heightman (236769), Paul Hemsley (4414534), Giuditta Illuzzi (11486395), Jordan Lane (11486398), Carrie Larner (11486401), Elisabetta Leo (16336), Lina Liu (227490), Andrew Madin (2369338), Scott Martin (8770), Lisa McWilliams (3115182), Mark J. O’Connor (512930), Jonathan P. Orme (2570623), Fiona Pachl (1643695), Martin J. Packer (1716334), Xiaohui Pei (8775905), Andrew Pike (689657), Marianne Schimpl (208250), Hongyao She (11486404), Anna D. Staniszewska (11486407), Verity Talbot (6084164), Elizabeth Underwood (9210380), Jeffrey G. Varnes (2499496), Lin Xue (826042), Tieguang Yao (9761206), Ke Zhang (115386), Andrew X. Zhang (1371321), Xiaolan Zheng (1638844) |
| سنة النشر: |
2021 |
| المجموعة: |
Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: |
Biochemistry, Genetics, Molecular Biology, Pharmacology, Cancer, Hematology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, overlapping hematological toxicities, good secondary pharmacology, brca mutant hbcx, brca mutant background, achieved regulatory approval, 17 pdx model, parp family members, oxo ‑ 5, dihydro ‑ 1, selective parp1 inhibitor, 25 , n <, highly selective, vivo efficacy, usually due, reduced effects, recent literature, preclinical species, physicochemical properties, parps poly, parp1 inhibition, line chemotherapies |
| الوصف: |
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro. |
| نوع الوثيقة: |
dataset |
| اللغة: |
unknown |
| Relation: |
https://figshare.com/articles/dataset/Discovery_of_5_4-_7-Ethyl-6-oxo_5_6-dihydro_1_5-naphthyridin-3-yl_methyl_piperazin-1-yl_i_N_i_methyl_pyridine-2-carboxamide_AZD5305_A_PARP1_DNA_Trapper_with_High_Selectivity_for_PARP1_over_PARP2_and_Other_PARPs/16688965 |
| DOI: |
10.1021/acs.jmedchem.1c01012.s002 |
| الاتاحة: |
https://doi.org/10.1021/acs.jmedchem.1c01012.s002 |
| Rights: |
CC BY-NC 4.0 |
| رقم الانضمام: |
edsbas.C5BC5FC9 |
| قاعدة البيانات: |
BASE |