Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor

Sperandio, David; Aktoudianakis, Vangelis; Babaoglu, Kerim; Chen, Xiaowu; Elbel, Kristyna M.; Chin, Gregory T.; Corkey, Britton K.; Du, Jinfa; Jiang, Bob; Kobayashi, Tetsuya; Mackman, Richard L.; Martinez, Ruben; Yan, Hai; Zablocki, Jeff; Kusam, Saritha; Jordan, Kim; Webb, Heather K.; Bates, Jamie; Lad, Latesh; Mish, Michael; Niedziela-Majka, Anita; Metobo, Sammy; Sapre, Annapurna; Hung, Magdeleine; Jin, Debi; Fung, Wanchi; Kan, Elaine; Eisenberg, Gene; Larson, Nate; Newby, Zachary E.; Lansdon, E.B.; Tay, Chin Hun; Neve, Richard M.; Shevick, Sophia L.; Breckenridge, David G.

doi:10.1016/j.bmc.2018.11.020

Cited by 12 publications

(5 citation statements)

References 23 publications

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“…GS-5829 is an oral small-molecule BET inhibitor that has been in development for the treatment of solid tumors, including CRPC, ER-positive advanced-stage breast cancer, and hematologic malignancies. Inhibition of cell growth and induction of apoptosis of solid and hematologic cancer in preclinical studies of GS-5829 ( 21 ), high potency and selectivity for BRD4 bromodomains ( 23 ), and favorable PK properties in preclinical models ( 23, 24 ) provided rationale for further clinical exploration in advanced cancers.…”

Section: Discussionmentioning

confidence: 99%

Phase Ib Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

Aggarwal

Starodub

Koh

et al. 2022

Clinical Cancer Research

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Purpose: A Phase 1b study (1604) was conducted to evaluate the safety and efficacy of GS-5829, an oral bromodomain and extra-terminal inhibitor, alone and in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). A Phase 1 study (1599) in solid tumors/lymphoma was also conducted. Patients and Methods: Men with confirmed mCRPC and disease progression despite abiraterone and/or enzalutamide treatment were enrolled in a 3 + 3 dose-escalation paradigm starting at 2 mg daily with GS-5829 alone and in combination with 160-mg daily enzalutamide. The primary efficacy endpoint was non-progression rate at Week 24; secondary endpoints included prostate-specific antigen (PSA) reduction from baseline, progression-free survival (PFS), and GS-5829 pharmacokinetics (PK). PK and safety were also evaluated in Study 1599. Results: Thirty-one men, with a median of 5 prior regimens, received at least 1 dose of study drug in Study 1604. Treatment-emergent adverse events (TEAEs) were reported in 94% of patients; 16% discontinued for TEAEs. There were no dose-dependent increases in the AUCtau or Cmax after once-daily administration of GS-5829 2 to 9 mg,and biomarkers CCR2 inhibition and HEXIM1 induction were increased only at higher doses of monotherapy. A high degree of interpatient variability existed across all doses in PK and pharmacodynamic parameters. The proportion with non-progression at Week 24, estimated by Kaplan-Meier model, was 25% (95% confidence interval [CI] 10, 42) for all treated patients. Conclusions: GS-5829 was generally tolerated but demonstrated limited efficacy and lack of dose-proportional increases in plasma concentrations in patients with mCRPC.

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Section: Discussionmentioning

confidence: 99%

Phase Ib Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

Aggarwal

Starodub

Koh

et al. 2022

Clinical Cancer Research

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“…[108] The benzimidazole-quinoline hybrids possessed considerable antiproliferative activity, and among them, hybrid 52 (IC 50 : 6.1-13.4 µM, MTT assay) was comparable to cabozantinib (IC 50 : 4.5-11.8 µM) against A549, MCF-7, and MKN-45 cancer cell lines. [109][110][111][112] Molecular docking study demonstrated that hybrid 52 could bind tightly with the active site of c-Met by various interactions, so this hybrid could serve as a promising candidate for the development of novel c-Met inhibitors.…”

Section: Miscellaneous Benzimidazole Hybridsmentioning

confidence: 99%

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

Feng

Cheng

et al. 2022

Archiv der Pharmazie

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Cancer, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth, remains a prominent cause of death across the world. Almost all currently available anticancer agents used in clinical practice have developed multidrug resistance, creating an urgent need to develop novel chemotherapeutics. Benzimidazole derivatives could exert anticancer properties through diverse mechanisms, inclusive of the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, antiangiogenesis, and blockage of glucose transport. Moreover, several benzimidazole-based agents have already been approved for the treatment of cancers. Hence, benzimidazole derivatives are useful scaffolds for the development of novel anticancer agents. In particular, benzimidazole hybrids could exert dual or multiple antiproliferative activities and had the potential to overcome drug resistance, demonstrating the potential of benzimidazole hybrids as potential prototypes for clinical deployment in the control and eradication of cancers. The purpose of the present review article is to provide a comprehensive landscape of benzimidazole hybrids as potential anticancer agents, and the structure-activity relationship as well as mechanisms of action are also discussed to facilitate the further rational design of more effective candidates, covering articles published from 2019 to 2021.

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“…In particular, isoxazolyl benzimidazole derivatives are used as analgesic and anti-inflammatory agents (Kankala et al, 2013). They are also potent and orally bioavailable bromodomain BET inhibitors (Sperandio et al, 2019). Given the wide range of therapeutic applications for such compounds, and in a continuation of the work already carried out on the synthesis of compounds resulting from 1,5-benzodiazepine (Chkirate et al, 2001(Chkirate et al, , 2019a(Chkirate et al, ,b,c, 2021, a similar approach gave the title compound, 6-methyl-2- [(5-methylisoxazol-3-yl)methyl]-1H-benzimidazole C 13 H 13 N 3 O (I).…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure, Hirshfeld surface analysis and density functional theory study of 6-methyl-2-[(5-methylisoxazol-3-yl)methyl]-1H-benzimidazole

Idrissi

Chkirate

Abad³

et al. 2021

Acta Crystallogr E Cryst Commun

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In the title molecule, C13H13N3O, the isoxazole ring is inclined to the benzimidazole ring at a dihedral angle of 69.28 (14)°. In the crystal, N—H...N hydrogen bonds between neighboring benzimidazole rings form chains along the a-axis direction. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...H (48.8%), H...C/C...H (20.9%) and H...N/N...H (19.3%) interactions. The optimized structure calculated using density functional theory at the B3LYP/6–311 G(d,p) level is compared with the experimentally determined structure in the solid state. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy gap is 4.9266 eV.

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Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor

Cited by 12 publications

References 23 publications

Phase Ib Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

Phase Ib Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

Crystal structure, Hirshfeld surface analysis and density functional theory study of 6-methyl-2-[(5-methylisoxazol-3-yl)methyl]-1H-benzimidazole

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