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Structural basis for the inhibition of poly(ADP-ribose) polymerases 1 and 2 by BMN 673, a potent inhibitor derived from dihydropyridophthalazinone.

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Aoyagi-Scharber M, Gardberg AS, Yip BK, Wang B, Shen Y, Fitzpatrick PA
OpenAccess logo Acta Crystallogr F Struct Biol Commun 70 1143-9 (2014)
Cited: 27 times
EuropePMC logo PMID: 25195882

Abstract

Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2), which are involved in DNA damage response, are targets of anticancer therapeutics. BMN 673 is a novel PARP1/2 inhibitor with substantially increased PARP-mediated tumor cytotoxicity and is now in later-stage clinical development for BRCA-deficient breast cancers. In co-crystal structures, BMN 673 is anchored to the nicotinamide-binding pocket via an extensive network of hydrogen-bonding and π-stacking interactions, including those mediated by active-site water molecules. The novel di-branched scaffold of BMN 673 extends the binding interactions towards the outer edges of the pocket, which exhibit the least sequence homology among PARP enzymes. The crystallographic structural analyses reported here therefore not only provide critical insights into the molecular basis for the exceptionally high potency of the clinical development candidate BMN 673, but also new opportunities for increasing inhibitor selectivity.

Articles - 4pjt mentioned but not cited (8)

  1. Life beyond the Tanimoto coefficient: similarity measures for interaction fingerprints. Rácz A, Bajusz D, Héberger K. J Cheminform 10 48 (2018)
  2. Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer. Fu L, Wang S, Wang X, Wang P, Zheng Y, Yao D, Guo M, Zhang L, Ouyang L. Sci Rep 6 3 (2016)
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  4. Structural basis for the inhibition of poly(ADP-ribose) polymerases 1 and 2 by BMN 673, a potent inhibitor derived from dihydropyridophthalazinone. Aoyagi-Scharber M, Gardberg AS, Yip BK, Wang B, Shen Y, Fitzpatrick PA. Acta Crystallogr F Struct Biol Commun 70 1143-1149 (2014)
  5. Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition. Ogden TEH, Yang JC, Schimpl M, Easton LE, Underwood E, Rawlins PB, McCauley MM, Langelier MF, Pascal JM, Embrey KJ, Neuhaus D. Nucleic Acids Res 49 2266-2288 (2021)
  6. The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors. Palve V, Knezevic CE, Bejan DS, Luo Y, Li X, Novakova S, Welsh EA, Fang B, Kinose F, Haura EB, Monteiro AN, Koomen JM, Cohen MS, Lawrence HR, Rix U. Cell Chem Biol 29 202-214.e7 (2022)
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  8. Design, Synthesis, and In Vitro Evaluation of the Photoactivatable Prodrug of the PARP Inhibitor Talazoparib. Li J, Xiao D, Liu L, Xie F, Li W, Sun W, Yang X, Zhou X. Molecules 25 407 (2020)


Reviews citing this publication (6)

  1. Understanding specific functions of PARP-2: new lessons for cancer therapy. Ali SO, Khan FA, Galindo-Campos MA, Yélamos J. Am J Cancer Res 6 1842-1863 (2016)
  2. Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. Wu Q, Qian W, Sun X, Jiang S. J Hematol Oncol 15 143 (2022)
  3. PARP1: Structural insights and pharmacological targets for inhibition. Spiegel JO, Van Houten B, Durrant JD. DNA Repair (Amst) 103 103125 (2021)
  4. PARP inhibitors as antitumor agents: a patent update (2013-2015). Yuan Z, Chen J, Li W, Li D, Chen C, Gao C, Jiang Y. Expert Opin Ther Pat 27 363-382 (2017)
  5. Development of the PARP inhibitor talazoparib for the treatment of advanced BRCA1 and BRCA2 mutated breast cancer. Hobbs EA, Litton JK, Yap TA. Expert Opin Pharmacother 22 1825-1837 (2021)
  6. A comprehensive look of poly(ADP-ribose) polymerase inhibition strategies and future directions for cancer therapy. Kumar C, Rani N, Velan Lakshmi PT, Arunachalam A. Future Med Chem 9 37-60 (2017)

Articles citing this publication (13)

  1. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, Kaye S, Sachdev J, Heymach J, Smith DC, Henshaw JW, Herriott A, Patterson M, Curtin NJ, Byers LA, Wainberg ZA. Cancer Discov 7 620-629 (2017)
  2. Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors. Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H. J Med Chem 60 1262-1271 (2017)
  3. Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma. Kizilbash SH, Gupta SK, Chang K, Kawashima R, Parrish KE, Carlson BL, Bakken KK, Mladek AC, Schroeder MA, Decker PA, Kitange GJ, Shen Y, Feng Y, Protter AA, Elmquist WF, Sarkaria JN. Mol Cancer Ther 16 2735-2746 (2017)
  4. PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier. Rom S, Zuluaga-Ramirez V, Reichenbach NL, Dykstra H, Gajghate S, Pacher P, Persidsky Y. J Neuroinflammation 13 254 (2016)
  5. AutoGrow4: an open-source genetic algorithm for de novo drug design and lead optimization. Spiegel JO, Durrant JD. J Cheminform 12 25 (2020)
  6. Characterization of the DNA dependent activation of human ARTD2/PARP2. Obaji E, Haikarainen T, Lehtiö L. Sci Rep 6 34487 (2016)
  7. Autonomous molecule generation using reinforcement learning and docking to develop potential novel inhibitors. Jeon W, Kim D. Sci Rep 10 22104 (2020)
  8. Active site fingerprinting and pharmacophore screening strategies for the identification of dual inhibitors of protein kinase C (ΡΚCβ) and poly (ADP-ribose) polymerase-1 (PARP-1). Chadha N, Silakari O. Mol Divers 20 747-761 (2016)
  9. Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1. Ryan K, Bolaňos B, Smith M, Palde PB, Cuenca PD, VanArsdale TL, Niessen S, Zhang L, Behenna D, Ornelas MA, Tran KT, Kaiser S, Lum L, Stewart A, Gajiwala KS. J Biol Chem 296 100251 (2021)
  10. Development of Novel Pyridine-Thiazole Hybrid Molecules as Potential Anticancer Agents. Ivasechko I, Yushyn I, Roszczenko P, Senkiv J, Finiuk N, Lesyk D, Holota S, Czarnomysy R, Klyuchivska O, Khyluk D, Kashchak N, Gzella A, Bielawski K, Bielawska A, Stoika R, Lesyk R. Molecules 27 6219 (2022)
  11. Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors. Zhao H, Ji M, Cui G, Zhou J, Lai F, Chen X, Xu B. Bioorg Med Chem 25 4045-4054 (2017)
  12. Talazoparib Does Not Interact with ABCB1 Transporter or Cytochrome P450s, but Modulates Multidrug Resistance Mediated by ABCC1 and ABCG2: An in Vitro and Ex Vivo Study. Sabet Z, Vagiannis D, Budagaga Y, Zhang Y, Novotná E, Hanke I, Rozkoš T, Hofman J. Int J Mol Sci 23 14338 (2022)
  13. Structural and biochemical analysis of the PARP1-homology region of PARP4/vault PARP. Frigon L, Pascal JM. Nucleic Acids Res 51 12492-12507 (2023)


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