Fragment-to-Lead Medicinal Chemistry Publications in 2021.

This Perspective is the seventh in an annual series that summarizes successful Fragment-to-Lead (F2L) case studies published in a given year. A tabulated summary of relevant articles published in 2021 is provided, and features such as target class, screening methods, and ligand efficiency are discussed, both for the 2021 examples and for the combined examples over the years 2015-2021. In addition, trends and new developments in the field are summarized. In particular, the use of structural information in fragment-based drug discovery is discussed.

A Snapshot of Female Representation in Twelve Academic Psychiatry Institutions Around the World.

The study presented here aims at bringing a global perspective to the phenomenon of unequal representation of females in science by offering empirical data of female representation in neuroscience/schizophrenia academic or clinical departments in several institutions around the world. We took advantage of a budding network of scientists and colleagues from different countries to bring the data together. The data presented are related to sex, that is the biological distinction between males and females, based on genetics and reproductive anatomy, while gender, considered a cultural concept was harder to determine. We report data from two clinical/academic departments in Nigeria, Africa; 2 clinical/academic departments from Sudan, Africa; 1 clinical/academic department from South Africa, Africa; 3 academic institutions from Ireland, Europe; 1 clinical/academic institution from Spain, Europe; 2 academic institutions from Buenos Aires University, Argentina; and the Psychiatry Departments at Harvard Medical School, Boston, USA.

Fragment-to-Lead Medicinal Chemistry Publications in 2020.

Fragment-based drug discovery (FBDD) continues to evolve and make an impact in the pharmaceutical sciences. We summarize successful fragment-to-lead studies that were published in 2020. Having systematically analyzed annual scientific outputs since 2015, we discuss trends and best practices in terms of fragment libraries, target proteins, screening technologies, hit-optimization strategies, and the properties of hit fragments and the leads resulting from them. As well as the tabulated Fragment-to-Lead (F2L) programs, our 2020 literature review identifies several trends and innovations that promise to further increase the success of FBDD. These include developing structurally novel screening fragments, improving fragment-screening technologies, using new computer-aided design and virtual screening approaches, and combining FBDD with other innovative drug-discovery technologies.

Telehealth-delivered, Cardioprotective Diet and Exercise Program for Liver Transplant Recipients: A Randomized Feasibility Study.

Rapid excess weight gain and metabolic complications contribute to poor outcomes following liver transplant care. Providing specialist lifestyle intervention with equitable access is a challenge for posttransplant service delivery. METHODS: This study investigated the feasibility of a 12-wk telehealth delivered lifestyle intervention for liver transplant recipients (randomized controlled trial with a delayed intervention control group). The intervention included 14 group sessions facilitated by nutrition and exercise specialists via video streaming telehealth and participants used their own devices. Feasibility was assessed across session attendance, the adequacy, acceptability, and confidence with the telehealth technology and adherence to diet (Mediterranean Diet Adherence Score). Secondary pooled analysis of effectiveness was determined from changes in quality of life and metabolic syndrome severity score. RESULTS: Of the 35 participants randomized, dropout was 22.8% (n = 8) and overall session attendance rate was 60%. Confidence with and adequacy of home technology was rated high in 96% and 91% of sessions, respectively. Participants randomized to the intervention significantly improved Mediterranean Diet Adherence Score (2-point increase [95% confidence interval, 1.5-3.4] versus control 0 point change [95% confidence interval, -1.4 to 1.2]; P = 0.004). Intervention (within group) analysis found the intervention significantly decreased the metabolic syndrome severity score (-0.4 [95% confidence interval, -0.6 to -0.1] P = 0.01), and improved mental health-related quality of life (2.5 [95% confidence interval, 0.4-4.6] P = 0.03). CONCLUSIONS: A cardioprotective lifestyle intervention delivered via telehealth is feasible for liver transplant recipients and may improve access to specialist care to support metabolic health and wellness after transplant.

Agreement and Reliability of Clinician-in-Clinic Versus Patient-at-Home Clinical and Functional Assessments: Implications for Telehealth Services.

OBJECTIVE: To compare agreement and reliability between clinician-measured and patient self-measured clinical and functional assessments for use in remote monitoring, in a home-based setting, using telehealth. DESIGN: Reliability study: repeated-measure, within-subject design. SETTING: Trained clinicians measured standard clinical and functional parameters at a face-to-face clinic appointment. Participants were instructed on how to perform the measures at home and to repeat self-assessments within 1 week. PARTICIPANTS: Liver transplant recipients (LTRs) (N=18) (52±14y, 56% men, 5.4±4.3y posttransplant] completed the home self-assessments. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The outcomes assessed were body weight, systolic and diastolic blood pressure (SBP and DBP), waist circumference, repeated chair sit-to-stand (STST), maximal push-ups, and the 6-minute walk test (6MWT). Intertester reliability and agreement between face-to-face clinician and self-reported home-based participant measures were determined by intraclass-correlation coefficients (ICCs) and Bland-Altman plots, which were compared with minimal clinically important differences (MCID) (determined a priori). RESULTS: The mean difference (95% confidence interval) and [limits of agreement] for measures (where positive values indicate lower participant value) were weight, 0.7 (0.01-1.4) kg [-2.2 to 3.6kg]; waist 0.4 (-1.2 to 2.0) cm [-5.9 to 6.8cm]; SBP 7.7 (0.6-14.7 ) mmHg [-19.4 to 34.9mmHg]; DBP 2.4 (-1.4 to 6.2 ) mmHg [-12.2 to 17.0mmHg]; 6MWT, 7.5 (-29.1 to 44.1) m [-127.3 to 142.4m]; STST 0.5 (-0.8 to 1.7) seconds [-4.3 to 5.3s]; maximal push-ups -2.2 (-4.4 to -0.1) [-10.5 to 6.0]. ICCs were all >0.75 except for STST (ICC=0.73). Mean differences indicated good agreement than MCIDs; however, wide limits of agreement indicated large individual variability in agreement. CONCLUSIONS: Overall, LTRs can reliably self-assess clinical and functional measures at home. However, there was wide individual variability in accuracy and agreement, with no functional assessment being performed within acceptable limits relative to MCIDs >80% of the time.

BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer.

PURPOSE: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor-positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC. EXPERIMENTAL DESIGN: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples. RESULTS: Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing fibroblast growth factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC. CONCLUSIONS: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.

Assessment of the Target Engagement and D-Serine Biomarker Profiles of the D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756.

Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar D-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.

Therapeutic Rationale to Target Highly Expressed CDK7 Conferring Poor Outcomes in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle-related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n = 383) and the METABRIC TNBC dataset (n = 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n = 109) and the METABRIC TNBC cohort (n = 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment. Cancer Res; 77(14); 3834-45. ©2017 AACR.

Diagnostic and Therapeutic Implications of Histone Epigenetic Modulators in Breast Cancer.

Breast cancer is the most common cancer in women and great advancements have been made for individualised patient treatment. Through understanding the underlying altered biology in the different subtypes of breast cancer, targeted therapeutics have been developed. Unfortunately, resistance to targeted therapy, intrinsic or acquired, is a recurring theme in cancer treatment. Epigenetic-mediated resistance to targeted therapy has been identified across different types of cancer. In addition, tumorigenesis has also been linked to altered expression of epigenetic modifiers. Due to the reversible nature of epigenetic modifications, epigenetic proteins are appealing as therapeutic targets in both the primary and relapsed/resistant setting. In this review, we will discuss the current state of targetable epigenetic histone modifications and their diagnostic and therapeutic implications in breast cancer.

A fragment-based approach to identifying S-adenosyl-l-methionine -competitive inhibitors of catechol O-methyl transferase (COMT).

Catechol O-methyl transferase belongs to the diverse family of S-adenosyl-l-methionine transferases. It is a target involved in the treatment of Parkinson's disease. Here we present a fragment-based screening approach to discover noncatechol derived COMT inhibitors which bind at the SAM binding pocket. We describe the identification and characterization of a series of highly ligand efficient SAM competitive bisaryl fragments (LE = 0.33-0.58). We also present the first SAM-competitive small-molecule COMT co-complex crystal structure.

Trimethylsilylpyrazoles as novel inhibitors of p38 MAP kinase: a new use of silicon bioisosteres in medicinal chemistry.

The synthesis, physicochemical properties and pharmacological profiles of two novel silicon-containing p38 MAP kinase inhibitors are described.

Stereochemical elucidation of the 1,4 polyketide amphidinoketide I.

The relative and absolute stereochemistry of amphidinoketide I has been determined by the total synthesis of all the diastereoisomers. Molecular modelling suggests that the natural product is not the thermodynamically preferred diastereoisomer.