Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.

The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations. The representative compound 10g exhibited excellent potency against wide type TRKA/C, TRKAG595R, TRKAG667C, and TRKAF589L with IC50 values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. 10g also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC50 values of 1.43-47.56 nM. Moreover, 10g demonstrated ideal antitumor efficacy in both BaF3-CD74-NTRK1G595R and BaF3-CD74-NTRK1G667C xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.

Application of deep generative model for design of Pyrrolo[2,3-d] pyrimidine derivatives as new selective TANK binding kinase 1 (TBK1) inhibitors.

The deep conditional transformer neural network SyntaLinker was applied to identify compounds with pyrrolo[2,3-d]pyrimidine scaffold as potent selective TBK1 inhibitor. Further medicinal chemistry optimization campaign led to the discovery of the most potent compound 7l, which exhibited strong enzymatic inhibitory activity against TBK1 with an IC50 value of 22.4 nM 7l had a superior inhibitory activity in human monocytic THP1-Blue cells reporter gene assay than MRT67307. Furthermore, 7l significantly inhibited TBK1 downstream target genes cxcl10 and ifnß expression in THP1 and RAW264.7 cells induced by poly (I:C) and lipopolysaccharide, respectively. This study suggested that combination of deep conditional transformer neural network SyntaLinker and transfer learning could be a powerful tool for scaffold hopping in drug discovery.

Deep learning-driven scaffold hopping in the discovery of Akt kinase inhibitors.

Scaffold hopping has been widely used in drug discovery and is a topic of high interest. Here a deep conditional transformer neural network, SyntaLinker, was applied for the scaffold hopping of a phase III clinical Akt inhibitor, AZD5363. A number of novel scaffolds were generated and compound 1a as a proof-of-concept was synthesized and validated by biochemical assay. Further structure-based optimization of 1a led to a novel Akt inhibitor with high potency (Akt1 IC50 = 88 nM) and in vitro antitumor activities.

TANK-binding kinase 1 (TBK1): An emerging therapeutic target for drug discovery.

Dysregulation of TANK-binding kinase 1 (TBK1) homeostasis leads to the occurrence and progression of many diseases, such as inflammation, autoimmune diseases, metabolic diseases, and cancer. Therefore, there is a need to develop TBK1 inhibitors as therapeutic agents. In this review, we highlight the diverse biological functions of TBK1 and summarize the promising small-molecule inhibitors of TBK1 that have the potential to be developed as therapeutic candidates.

The complete genome sequence of Escherichia phage SRT7, a novel T7-like phage.

In this study, we isolated a novel virulent Escherichia phage, SRT7. Its genome is a double-stranded linear DNA molecule containing 39,883 bp. Direct terminal repeats with a length of 175 bp, are present at both ends of the genome. The G+C content is 50.54%. Forty-seven putative protein coding genes were identified. No tRNA or rRNA genes were identified. Comparative genomic analysis revealed that phage SRT7 is a novel member of the T7-like phage cluster, but it forms a singleton subcluster.

Complete genome sequence of SRT8, a novel T1-like Escherichia coli bacteriophage.

In this study, an Escherichia coli virulent phage, SRT8, was isolated from sewage sludge samples collected from Jinan, Shandong Province, China. The genome of phage SRT8 consists of 49,579 bp with 47.83% G+C content. The phage genome contains 84 putative protein-coding genes, and no rRNA or tRNA genes. Comparative genomics analysis showed that the E. coli phage SRT8 is a member of a new species and belongs to the subfamily Tunavirinae, which includes T1-like phages.

[Radiofrequency catheter ablation of the premature ventricular contractions originating from His bundle region].

OBJECTIVE: To explore the electrocardiogram and 3-dimensional electroanatomic mapping features and radiofrequency catheter ablation efficacy of patients with premature ventricular contractions (PVCs ) originating from His bundle region. METHODS: Between February 2009 and February 2011, 10 consecutive patients ( 4 male, aged from 19 to 59 years) who underwent ablation for frequent PVCs originating close to His bundle region in our department were included. Electroanatomic mapping of RVOT and ASC, ablation was performed with the 7F 4-mm-tip ablation catheter. RESULTS: Among these 10 patients with PVCs originating from His bundle region, 6 originated from the RVOT, 1 from NCC and 3 from RCC. Eight patients showed LBBB morphology,1 patient with PVCs originated from RCC and 1 patient with PVCs originated from NCC showed RBBB morphology. At the successful ablation sites, local ventricular activation v wave was detected 22-52 (32.6 ± 10.2) ms earlier than the QRS wave in the surface electrocardiogram. The distance between target and His bundle was 5.0-8.4(7.0 ± 1.1)mm. Ablation was successful in all 10 patients without complications (PVCs < 500 beats/24 h post ablation). CONCLUSION: PVCs originating near the His bundle have similar electrocardiographic and electrophysiological characteristics for PVSc originated from the RVOT or ASC. Because of the close anatomical relationship between RVOT and ASC, it is necessary to mapping both RVOT and ASC to accurately identify the site of PVCs origin and to guild successful ablation.

[Preferential conduction to right ventricular outflow track leads to left bundle-branch block morphology in patient with premature ventricular contraction originating from the aortic sinus cusp].

OBJECTIVE: The purpose of this study was to explore the relationship between originate and breakout and radiofrequency catheter ablation strategy in patients undergoing radiofrequency ablation for premature ventricular contractions originating from the aortic sinus cusp (ASC) using 3-dimensional electro anatomic mapping. METHODS: This study included 21 consecutive patients (10 male) underwent ablation for frequent PVCs originating from ASC in our hospital between May 2009 and February 2012. Electro anatomic mapping and ablation of right ventricular outflow track (RVOT) and left ventricular outflow track (LVOT) were performed with the 7F 4-mm-tip ablation catheter from right femoral vein and artery. Activation mapping and pacing mapping were performed in all patients. RESULTS: Ablation was successful in all 21 patients successful ablation target in left coronary sinus cusp (LCC, n = 17), in right coronary sinus cusp (RCC, n = 2) and in noncoronary sinus cusp (NCC, n = 2). Seven patients showed a RBBB morphology (group A) and 14 patients showed a LBBB morphology (group B). In group A, earliest ventricular activation (EVA) was recorded 22 - 34 (27.4 ± 4.6) ms earlier before QRS at the site of catheter ablation in ASC. In group B, EVA was later in RVOT than that in ASC in 5 patients and EVA at the site of catheter ablation in RVOT and ASC was 22 - 28 (25.2 ± 2.7) ms and 26 - 40 (32.8 ± 5.2) ms, respectively (t = -3.6, P = 0.024) while EVA was earlier in the remaining 9 patients and EVA recorded in RVOT and ASC was 22 - 38 (28.7 ± 5.9) ms and 18 - 28 (22.7 ± 3.6) ms, respectively (t = 3.8, P = 0.005). CONCLUSION: Patients with premature ventricular contractions originating from the ASC often show preferential conduction to the RVOT, which may explain the LBBB morphology of ECG in these patients.

Digoxin may reduce the mortality rates in patients with congestive heart failure.

Digoxin has been used to treat congestive heart failure (CHF) for more than two centuries. It's clinical efficacy, however, has been under question in recent years because recent clinical trials showed that digoxin therapy in CHF patients was associated with no beneficial effects in mortality, but only a modest reduction in clinical symptoms and the frequency of heart failure related hospitalisation. Digoxin's effect on mortality seems closely related to its serum concentrations; high serum concentrations (e.g. >or=1.2 ng/ml) have been found to increase the risk of all-cause mortality in heart failure patients. Digoxin-associated risk in mortality may be due to an increases in myocardial oxygen consumption and arrhythmogenesis at higher serum concentrations. We hypothesized that the serum concentration of digoxin is a major determinant factor of its efficacy on mortality rates in patients with congestive heart failure. The maintenance of digoxin's serum concentration at the lower end of the reference range, i.e., between 0.5 and 0.8 ng/ml, may reduce mortality rates as well as improve clinical symptoms.

Long-term follow-up of patients with P-R prolongation after catheter ablation of slow pathway for atrioventricular node re-entrant tachycardia.

BACKGROUND: Long-term impact of interval between P wave and R wave (P-R) prolongation on prognosis of patients with successful catheter ablation of slow atrioventricular nodal pathway was investigated. METHODS: Among 436 patients undergoing slow-pathway ablation for atrioventricular node re-entrant tachycardia (AVNRT), 17 (3.9%) experienced permanent P-R prolongation. Ablation target sites where conduction block was induced were located in mid- or anteroseptum. Fast junctional rhythm with ventriculoatrial conduction block was observed in eight patients immediately before atrioventricular block. RESULTS: Antegrade slow-pathway conduction was eliminated in 16 patients, and retrograde fast- and slow-pathway conduction was abolished in all patients. There was no recurrence of AVNRT after an average of 38 +/- 12 month follow-up. There was no deterioration of atrioventricular block in these patients. Average PR interval prior to hospital discharge and at the end of follow-up was 0.24 +/- 0.02 sec and 0.23 +/- 0.02 sec, respectively (p >0.05). Left ventricular ejection fraction remained unchanged in these patients (p >0.05). CONCLUSIONS: Radiofrequency catheter ablation of slow pathway for AVNRT is associated with a small risk of atrioventricular block. PR prolongation after successful slow-pathway ablation is associated with benign prognosis.

Simplified approach to radiofrequency catheter ablation of paroxysmal supraventricular tachycardia.

AIM: To investigate the safety and efficacy of a simplified approach in radiofrequency catheter ablation of paroxysmal supraventricular tachycardia. METHODS: The study involved 239 patients (118 men and 121 women) with paroxysmal supraventricular tachycardia and normal 12-lead electrocardiographic (ECG) findings at sinus rhythm, who visited the Cardiology Department of Weifang Medical College Hospital between January 2000 and September 2003. The mean age of patients was 39.2+/-11.9 years. The patients were divided into two groups: one undergoing a conventional 5-catheter ablation (controls), and the other a simplified 3-catheter ablation (study group). The follow up after ablation lasted 12 months. No antiarrhythmic agents were prescribed to the patients with successful ablation. RESULTS: The conventional and the 3-catheter ablation group did not differ in ablation success (97.5% vs 98.3%, p=0.42) and recurrence of paroxysmal supraventricular tachycardia (2.5% vs 3.3%, p=0.23). The simplified approach was associated with a significantly shorter procedure duration (89.1+/-28.2 vs 96.1+/-21.2 minutes, p<0.01) and fluoroscopy time (10.7+/-2.6 vs 12.7+/-4.2 minutes, p<0.01). There were no significant differences between the two groups in the type and incidence of procedural complications and ablation success. CONCLUSIONS: The simplified 3-catheter ablation approach proved to be a safe and effective method for ablation of paroxysmal supraventricular tachycardia. However, further studies including larger sample of such patients are needed to assess the clinical outcomes and cost-effectiveness of this simplified procedure.

Management of cardiovascular risk factors in type 2 diabetic patients undergoing coronary angiography.

AIM: To investigate risk factor management in diabetic patients undergoing coronary angiography. METHODS: Hemoglobin (Hgb) A1c, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), blood pressure (BP), and body mass index (BMI) were cardiovascular risk factors analyzed in 284 consecutive type 2 diabetic patients who underwent coronary angiography. RESULTS: Coronary artery disease (CAD) was identified in 233 (82.0%) diabetic patients. The mean HgbA1c fraction for all patients at hospital admission was 9.7+/-1.4%. The mean concentration of LDL-C, HDL-C, and triglycerides was 2.82+/-0.9, 0.92+/-0.28, and 2.56+/-0.81 mmol/L, respectively. One hundred and twenty-two (43.0%) patients had LDL-C <2.6 mmol/L, 70 (24.7%) patients had a blood pressure of less than 130/85 mm Hg, and 158 (55.7%) had BMI <30 kg/m(2). Only 26 (9.1%) patients had optimal control of the above cardiac risk factors. The average LDL-C, triglycerides, and blood pressure in patients with severe coronary artery disease were higher than those in patients with moderate to mild coronary artery disease (p<0.01; unpaired t-test). CONCLUSIONS: Cardiovascular risk factors were poorly controlled in type 2 diabetic patients. The average LDL-C, triglycerides, and blood pressure in patients with severe coronary artery disease were higher than those in patients with moderate to mild coronary artery disease.