Journal ArticleDOI
Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.
Monica Bubenik,Pavel Mader,Philippe Mochirian,Frederic Vallee,Jill E. Clark,Jean-François Truchon,Alexander L. Perryman,Victor Pau,Igor Kurinov,Karl E. Zahn,Marie-Eve Leclaire,Robert Papp,Marie-Claude Mathieu,Martine Hamel,Nicole M. Duffy,Claude Godbout,Matias Casás-Selves,Jean-Pierre Falgueyret,Prasamit S Baruah,Olivier Nicolas,Rino Stocco,Hugo Poirier,Giovanni Martino,A. Fortin,Anne Roulston,Amandine Chefson,Stéphane Dorich,Miguel St.-Onge,Purvish P. Patel,Charles Pellerin,Stephane Ciblat,Thomas Pinter,Francis Barabé,Majida El Bakkouri,Paranjay Parikh,Christian Gervais,Agnel Sfeir,Yael Mamane,Stephen Morris,W. Cameron Black,Frank Sicheri,Michel Gallant +41 more
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TLDR
A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods and ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2-/- mouse tumor xenograft model.Abstract:
DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2-/- mouse tumor xenograft model.read more
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RHINO restricts MMEJ activity to mitosis
Alessandra Brambati,Olivia Sacco,Sarina Y. Porcella,Joshua Heyza,Mike Kareh,Jens C. Schmidt,Agnel Sfeir +6 more
TL;DR: In this paper , the authors used CRISPR/Cas9-based synthetic lethal screens to identify subunits of the 9-1-1 complex (RAD9A-HUS1-RAD1) and its interacting partner, RHINO, as critical MMEJ factors.
Journal ArticleDOI
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TL;DR: In this article , the authors discuss unique biochemical properties and structural features of DNA polymerase θ, its multiple roles in protection of genome stability and the potential of Pol θ as a target for cancer treatment.
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Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy
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TL;DR: The first proof of concept for the effectiveness of synthetic lethality (SL) was provided by the approval of poly(ADP-ribose)polymerase inhibitors, which exploit a SL interaction in BRCA-deficient cells, although their use is limited by resistance as discussed by the authors .
Journal ArticleDOI
Polθ Inhibition: An Anticancer Therapy for HR-Deficient Tumours
TL;DR: In this paper , the authors describe the significance of DNA polymerase theta and the Polθ-mediated TMEJ pathway and summarize the current state-of-the-art inhibitors and emphasize the promising role of Pol θ as a therapeutic target.
Posted ContentDOI
Cryo-EM structure of DNA polymerase θ helicase domain in complex with inhibitor novobiocin
Hanbo Guo,Yanxia Wang,Jun Mao,Huimin Zhao,Yuntong He,Yuandong Hu,Jian Li,Yujie Liu,Zheng Guan,Allen Guo,X. Ni,Fengying Zhang,Jie Heng +12 more
TL;DR: In this paper , the authors showed that the antibiotics novobiocin (NVB) noncompetitively inhibit ATP hydrolysis by the ATPase domain of the DNA Polymerase theta (Polθ-HLD).
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Journal ArticleDOI
Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair
Raphael Ceccaldi,Jessica Liu,Ravindra Amunugama,Ildiko Hajdu,Benjamin Primack,Mark I.R. Petalcorin,Kevin W O'Connor,Panagiotis A. Konstantinopoulos,Stephen J. Elledge,Simon J. Boulton,Timur Yusufzai,Alan D. D'Andrea +11 more
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Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.
Monica Bubenik,Pavel Mader,Philippe Mochirian,Frederic Vallee,Jill E. Clark,Jean-François Truchon,Alexander L. Perryman,Victor Pau,Igor Kurinov,Karl E. Zahn,Marie-Eve Leclaire,Robert Papp,Marie-Claude Mathieu,Martine Hamel,Nicole M. Duffy,Claude Godbout,Matias Casás-Selves,Jean-Pierre Falgueyret,Prasamit S Baruah,Olivier Nicolas,Rino Stocco,Hugo Poirier,Giovanni Martino,A. Fortin,Anne Roulston,Amandine Chefson,Stéphane Dorich,Miguel St.-Onge,Purvish P. Patel,Charles Pellerin,Stephane Ciblat,Thomas Pinter,Francis Barabé,Majida El Bakkouri,Paranjay Parikh,Christian Gervais,Agnel Sfeir,Yael Mamane,Stephen Morris,W. Cameron Black,Frank Sicheri,Michel Gallant +41 more