Structural and biochemical insights into purine-based drug molecules in hBRD2 delineate a unique binding mode opening new vistas in the design of inhibitors of the BET family.

Article

Author: Subramanya, Hosahalli ; Mahalingaswamy, Mahesh ; Arole, Aishwarya H ; Deshmukh, Prashant ; Dalavaikodihalli Nanjaiah, Nandakumar ; Sridhar, Ashok ; Mathur, Shruti ; Padmanabhan, Balasundaram

The bromodomain and extra-terminal (BET) family proteins, which are involved in chromatin function, have been shown to be promising drug targets in several pathological conditions, including cancer and inflammation. There is considerable interest in the development of BET inhibitors with novel scaffolds to modulate the epigenesis of such diseases. Here, high-resolution crystal structures of the purine class of FDA-approved drugs (theophylline, doxophylline and acyclovir) and non-FDA-approved compounds (3-methyl-7-propylxanthine and theobromine) complexed with hBRD2 bromodomains BD1 and BD2 are reported. Remarkably, a new binding site is exhibited by stacking the compounds against the WPF shelf of BD1 and BD2. This serendipitous binding, in addition to the known acetyl-lysine binding site, sufficiently anchors the ligands in the solvent-exposed region. In addition, slight variations in the lipophilicity of these molecules significantly affected the in vitro binding affinity and selectivity towards BD1 compared with BD2. This idiosyncratic binding provides a new structural framework to link these sites for the development of next-generation inhibitors of the BET family.

01 Nov 2022·Journal of Clinical Psychopharmacology

Effects of Treatment of Acute Major Depressive Episodes in Bipolar I Versus Bipolar II Disorders With Quetiapine

Review

Author: Tondo, Leonardo ; Miola, Alessandro ; Baldessarini, Ross J.

AbstractBackgroundSeveral second-generation antipsychotic drugs (SGAs) have evidence of benefit for acute major depressive episodes in bipolar disorder (BD) patients. However, their comparative efficacy in types I vs II BD (BD1 vs BD2) remains uncertain.MethodsWe carried out a systematic literature search for randomized, double-blinded, controlled treatment trials for acute major depressive episodes involving head-to-head comparisons of BD1 versus BD2 subjects, followed by meta-analyses and meta-regression modeling.ResultsSeven reports met out inclusion criteria, yielding 22 comparisons of SGA versus placebo averaging 8.3 weeks in duration. All trials involved quetiapine, which was much more effective than placebo (pooled standardized mean difference [SMD] = 1.76 [95% confidence interval, 1.40–2.12], P < 0.0001). Estimated % improvement averaged 53.5% [46.5–60.5] with quetiapine vs 39.8% [34.2–45.4] with placebo (P < 0.0001); their ratio was somewhat larger with BD1 (1.56 [1.26–1.86]) versus BD2 subjects (1.22 [1.07–1.37], P = 0.04; as was SMD (BD1: 2.35 [1.83–2.86]; BD2: SMD = 1.44 [1.05–1.82]). Meta-regression found diagnosis (BD1 > BD2) to be the only factor significantly associated with the meta-analytic outcome.ConclusionsAlthough data are limited, depressed BD1 patients may respond somewhat better to quetiapine than BD2. Additional head-to-head diagnostic comparisons are needed with other SGAs, as well as evaluation of monotherapy versus various combinations that include SGAs in both short- and long-term use.

03 Aug 2020·BJS OpenQ3 · MEDICINE

Prognostic and predictive values of tumour budding in stage IV colorectal cancer

Q3 · MEDICINE

ArticleOA

Author: Kajiwara, Y ; Hase, K ; Nagata, K ; Shiraishi, T ; Shinto, E ; Okamoto, K ; Ueno, H ; Mochizuki, S ; Yamadera, M ; Kishi, Y

AbstractBackgroundTumour budding is an important prognostic feature in early-stage colorectal cancer, but its prognostic significance in metastatic disease has not been fully investigated.MethodsPatients with stage IV disease who had primary colorectal tumour resection without previous chemotherapy or radiotherapy from January 2000 to December 2018 were reviewed retrospectively. Budding was evaluated at the primary site and graded according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) (BD1, low; BD2, intermediate; BD3, high). Patients were categorized by metastatic (M1a, M1b) and resectional (R0/R1, R2/unresected) status. Subgroups were compared for overall (OS) and recurrence-free (RFS) survival in R0/R1 subgroups; R2/unresected patients were evaluated for the rate of tumour progression, based on change in tumour size from baseline.ResultsOf 371 patients observed during the study, 362 were analysed. Patients with BD3 had a lower 5-year OS rate than those with BD1 + BD2 (18·4 versus 40·5 per cent; P < 0·001). Survival analyses according to metastatic and resection status also showed that BD3 was associated with shorter OS than BD1 + BD2. In multivariable analysis, BD3 (hazard ratio (HR) 1·51, 95 per cent c.i. 1·11 to 2·10; P = 0·009), T4 status (HR 1·39) and R2/unresected status (HR 3·50) were associated with decreased OS. In the R0/R1 subgroup, the 2-year RFS rate was similar for BD3 and BD1 + BD2 according to metastatic status. There was no significant difference between BD3 and BD1 + BD2 for change in tumour size in the R2/unresected subgroup (P = 0·094). Of 141 patients with initially unresectable metastases who had chemotherapy, 35 achieved conversion from unresectable to resectable status. The conversion rate was significantly higher for BD1 + BD2 than for BD3 (36 versus 18 per cent; P = 0·016).ConclusionStage IV colorectal cancer with high-grade tumour budding according to ITBCC criteria correlates with poor prognosis.

100 Deals associated with BD2

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	IL	Biolojic Design Ltd.	04 Jul 2024

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