Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology.

Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non-small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer.

Reversible male contraception by targeted inhibition of serine/threonine kinase 33.

Men or mice with homozygous serine/threonine kinase 33 () mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability.

Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that and expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value.

DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors.

The development of SARS-CoV-2 main protease (M) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate M inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of M. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M with low nanomolar K values.

Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.

BRDT, BRD2, BRD3, and BRD4 comprise the bromodomain and extraterminal (BET) subfamily which contain two similar tandem bromodomains (BD1 and BD2). Selective BD1 inhibition phenocopies effects of tandem BET BD inhibition both in cancer models and, as we and others have reported of BRDT, in the testes. To find novel BET BD1 binders, we screened >4.

DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 M inhibitors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (M) without extensive and time-consuming medicinal chemistry.

Mitogen-induced transcriptional programming in human fibroblasts.

Treatment of serum-starved quiescent human cells with fetal bovine serum (FBS), epidermal growth factor (EGF), or the phorbol ester (12-O-tetradecanoylphorbol-13-acetate, TPA) activates the RAS-MAPK pathway which initiates a transcriptional program which drives cells toward proliferation. Stimulation of the RAS-MAPK pathway activates mitogen- and stress-activated kinases (MSK) 1 and 2, which phosphorylate histone H3 at S10 (H3S10ph) or S28 (H3S28ph) (nucleosomal response) located at the regulatory regions of immediate-early genes, setting in motion a series of chromatin remodeling events that result in transcription initiation. To investigate immediate-early genes regulated by the MSK, we have completed transcriptome analyses (RNA sequencing) of human normal fibroblast cells (CCD-1070Sk) stimulated with EGF or TPA ± H89, a potent MSK/PKA inhibitor.

Discovery and characterization of bromodomain 2-specific inhibitors of BRDT.

Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile.

Updates on "Cancer Genomics and Epigenomics".

The field of "Cancer Genomics and Epigenomes" has been widely investigated for their involvement in cancer to understand the basic processes of different malignancies. The aggregation of genetic and epigenetic alterations also displays a wide range of heterogeneity making it quite necessary to develop personalized treatment strategies. The complex interplay between DNA methylation and chromatin dynamics in malignant cells is one of the major epigenetic mechanisms that lead to gene activation and repression.

Reinforcing vasal suture technique improves sperm concentration and pregnancy rates in men undergoing vasovasostomy for vasectomy reversal.

Background: Vasovasostomy (VV) is a well-described surgical technique with few notable modifications since microsurgical adaptation in the 1970s. Although contemporary reversal success rates are 70-90%, these most often are based on a lenient definition of >0 sperm (patency) and include only VV procedures. With stricter definitions, success rates drop >30%.

The Etiology of Peyronie's Disease: Pathogenesis and Genetic Contributions.

Introduction: Peyronie's disease (PD) is a chronic fibrosing condition that contributes to penile deformity, curvature, and pain. Initial familial studies demonstrated potential genetic links to PD. Since that time, very few investigations have significantly advanced the science in this area.

Efficacy of Combined Collagenase Clostridium histolyticum and RestoreX Penile Traction Therapy in Men with Peyronie's Disease.

Background: Previous studies of penile traction therapy (PTT) devices have demonstrated limited/no efficacy when combined with intralesional therapies for Peyronie's disease (PD). Recently, randomized data have demonstrated the efficacy of a novel PTT device, RestoreX, developed in cooperation with the Mayo Clinic, in men with PD.

Aim: To assess the safety and efficacy of treatment with the RestoreX device plus collagenase Clostridium histolyticum (CCH) compared with CCH alone and CCH with other PTT devices.

Safety and Efficacy of Collagenase Clostridium Histolyticum in Peyronie's Disease Men With Ventral Curvatures.

Objective: To evaluate the safety and efficacy of collagenase clostridium histolyticum (CCH) in men with ventral penile curvatures secondary to Peyronie's Disease (PD).

Methods: A prospective registry has been maintained of PD men undergoing CCH at our institution. Curvature assessments and subjective questioning were obtained at baseline and following 2 and 4 injection series.

Correlation of Hormone Receptor and Human Epidermal Growth Factor Receptor-2/neu Expression in Breast Cancer with Various Clinicopathologic Factors.

Background: A significant development in the breast carcinoma management is the correlation between the presence of hormone receptors in the tumor and response to hormonal therapy and chemotherapy. Human epidermal growth factor receptor-2/neu (Her-2/neu) overexpression also serves as a very useful parameter to predict response to herceptin.

Aim Of Study: The study was conducted to correlate immunohistochemical expression of markers such as estrogen receptor (ER), progesterone receptor (PR), and Her-2/neu with various clinicopathologic parameters.

Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update.

Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis.

Mitogen-induced distinct epialleles are phosphorylated at either H3S10 or H3S28, depending on H3K27 acetylation.

Stimulation of the MAPK pathway results in mitogen- and stress-activated protein kinase 1/2 (MSK1/2)-catalyzed phosphorylation of histone H3 at serine 10 or 28 and expression of immediate-early (IE) genes. In 10T1/2 mouse fibroblasts, phosphorylation of H3S10 and H3S28 occurs on different H3 molecules and in different nuclear regions. Similarly, we show that mitogen-induced H3S10 and H3S28 phosphorylation occurs in separate pools in human primary fibroblasts.

Grading systems in the cytological diagnosis of breast cancer: a review.

In developing countries, diagnosis of breast carcinoma is still made on fine-needle aspiration cytology (FNAC). For the resource-poor settings, FNAC is cheaper, less invasive and can sample different areas of the lesion compared with core needle biopsy. The role of breast FNA is usually limited to just categorize the lesion as benign or malignant.

A multigenic approach to evaluate genetic variants of PLCE1, LXRs, MMPs, TIMP, and CYP genes in gallbladder cancer predisposition.

Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment, and poor prognosis. The disease shows complex interplay between multiple genetic variants. We analyzed 15 polymorphisms in nine genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk.

CYP17 polymorphism (rs743572) is associated with increased risk of gallbladder cancer in tobacco users.

Gallbladder cancer (GBC) involves interplay of sex steroids, including estrogen and progesterone. Since CYP17 is a key enzyme involved in estrogen and testosterone hormone biosynthesis as well as in xenobiotic metabolism, it may be a potential candidate gene in the carcinogenesis of the gallbladder. Hence, the present study aimed to investigate the association of CYP17 (rs2486758, and rs743572) polymorphisms with GBC susceptibility.

Death receptor (DR4) haplotypes are associated with increased susceptibility of gallbladder carcinoma in north Indian population.

Background And Aim: Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4, FAS) and their ligands (TRAIL, FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis.

Association of adrenergic receptor gene polymorphisms in gallbladder cancer susceptibility in a North Indian population.

Purpose: Gallbladder cancer (GBC), the most common gastrointestinal and biliary tract malignancy, often coincides with gallstone disease (GSD). The genetic variants of adrenergic receptor (ADR) have been previously reported to be associated with hypomotility disorder of cardiovascular system and GSD. Since GSD may function as GBC precursor, the present study aimed to investigate the association of common functional genetic variants of ADRA2A C-1291G, ADRβ3 T190C or Trp64Arg, and ADRβ1 C1165G or Arg389Gly with GBC and GSD susceptibility.

Association of genetic variants of xenobiotic and estrogen metabolism pathway (CYP1A1 and CYP1B1) with gallbladder cancer susceptibility.

Gallbladder carcinoma is a highly aggressive cancer with female predominance. Interindividual differences in the effectiveness of the activation/detoxification of environmental carcinogens and endogenous estrogens may play a crucial role in cancer susceptibility. The present study included 410 patients with carcinoma of the gallbladder (GBC) and 230 healthy subjects.