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Discovery of ligands for TRIM58, a novel tissue selective E3 ligase
No full textRedirecting E3 ligases to neo-substrates leading to their proteasomal disassembly, known as targeted protein degradation (TPD), has emerged as a promising alternative to traditional, occupancy driven pharmacology. Although the field has expanded tremendously over the last years, the choice of E3 ligases remains limited, with an almost exclusive focus on CRBN and VHL. Here, we report the discovery of novel ligands to the PRY-SPRY domain of TRIM58, a RING ligase that is specifically expressed in erythroid precursor cells. A DSF screen, followed by validation using additional biophysical methods, led to the identification of the TRIM58 ligand TRIM-473. A basic SAR around the chemotype was established by utilizing a competitive binding assay employing a short FP pep-tide probe derived from an endogenous TRIM58 substrate. The X-ray co-crystal structure of TRIM58 in complex with TRIM-473 gave insights to the binding mode and potential exit vectors for bifunctional degrader design
Design of a Super-Soft Topical JAK Inhibitor, which Is Efficacious in Human Skin but Rapidly Deactivated in Blood
No full textWe describe the discovery and characterization of the super-soft topical JAK inhibitor 3(R), which is potent in biochemical and cellular assays as well as in human skin models. In blood, the neutral ester 3(R) is rapidly hydrolyzed (t1/2~6 min) to the corresponding charged carboxylic acid 4 exhibiting >30-fold reduced permeability. Consequently, acid 4 does not reach the intracellular JAK kinases and is inactive in cellular assays and in blood. Thus, hydrolysis by blood esterases leads to the rapid deactivation of the topically active ester 3(R) at a rate beyond the maximal hepatic clearance
Mechanism of Resistance to the WDR5 Inhibitor in MLL-Rearranged Leukemia.
No full textDrug resistance is a major problem often limiting the long-term effectiveness of targeted cancer therapeutics. Resistance can be acquired through mutations or amplification of the primary drug targets or activation of bypass signaling pathways. Considering the multifaceted function of WDR5 in human malignancies, WDR5 has emerged as an attractive drug target for the discovery of small-molecule inhibitors. In this study, we investigated if cancer cells might develop resistance to a highly potent WDR5 inhibitor. We established a drug-adapted cancer cell line and discovered that WDR5P173L mutation occurs in the resistant cells, which confers resistance by preventing target engagement of the inhibitor. This work elucidated the WDR5 inhibitor's potential resistance mechanism in a preclinical study as a reference for future study in the clinical stage
Therapeutic strategies targeting pro-fibrotic macrophages in interstitial lung disease.
No full textIdiopathic pulmonary fibrosis (IPF) is the representative phenotype of interstitial lung disease where severe scarring develops in the lung interstitium. Although antifibrotic treatments are available and have been shown to slow the progression of IPF, improved therapeutic options are still needed. Recent data indicate that macrophages play essential pro-fibrotic roles in the pathogenesis of pulmonary fibrosis. Historically, macrophages have been classified into two functional subtypes, "M1" and "M2," and it is well described that "M2" or "alternatively activated" macrophages contribute to fibrosis via the production of fibrotic mediators, such as TGF-β, CTGF, and CCL18. However, highly plastic macrophages may possess distinct functions and phenotypes in the fibrotic lung environment. Thus, M2-like macrophages in vitro and pro-fibrotic macrophages in vivo are not completely identical cell populations. Recent developments in transcriptome analysis, including single-cell RNA sequencing, have attempted to depict more detailed phenotypic characteristics of pro-fibrotic macrophages. This review will outline the role and characterization of pro-fibrotic macrophages in fibrotic lung diseases and discuss the possibility of treating lung fibrosis by preventing or reprogramming the polarity of macrophages. We also utilized a systematic approach to review the literature and identify novel and promising therapeutic agents that follow this treatment strategy
Effect of Sclerostin Inactivation in a Mouse Model of Severe Osteogenesis Imperfecta
No full textOsteogenesis imperfecta (OI) is a rare bone disease that is associated with fractures and low bone mass. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in OI. We had previously found that in Col1a1Jrt/+ mice, a model of severe OI, anti-sclerostin antibodies had a minimal skeletal effect. In the present study, we assessed the effect of genetic inactivation of sclerostin in the Col1a1Jrt/+ mouse. We crossed Col1a1Jrt/+ mice with Sost knockout mice to generate Sost-deficient Col1a1Jrt/+ mice and assessed differences between Col1a1Jrt/+ mice with homozygous Sost deficiency and Col1a1Jrt/+ mice with heterozygous Sost deficiency. We found that Col1a1Jrt/+ mice with homozygous Sost deficiency had higher body mass, femur length, trabecular bone volume, cortical thickness and periosteal diameter as well as increased biomechanical parameters of bone strength. Differences between genotypes were larger at the age of 14 weeks than at 8 weeks of age. Transcriptome analysis of RNA extracted from the tibial diaphysis revealed only 5 differentially regulated genes. Thus, genetic inactivation of Sost increased bone mass and strength in the Col1a1Jrt/+ mouse. It appears from these observations that the degree of Sost suppression that is required for eliciting a beneficial response can vary with the genetic cause of OI
Alternative synthesis of 5-(1H-Pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol
No full textSpinal Muscular Atrophy (SMA) is a heritable cause of infant mortality in 1/6000 births. The majority of patients with Type 1 SMA die by age of 22 months unless they receive intensive supportive care intervention, which can prolong life but does not reverse the loss of skeletal muscle function. Thus infants with Type 1 SMA have the most to gain by a potential Survival Motor Neuron (SMN) gene splice modulator such as BRANAPLAM. BRANAPLAM showed increased exon 7 inclusion and upregulated SMN protein expression in both SMA patient fibroblasts and SMNΔ7 5025-mouse myoblasts. Herein we describe the chemical synthesis of this compound for toxicological as well as clinical studies.
The original synthesis utilized sequential Suzuki cross-couplings to form biaryl intermediates 4’ and 6’, which is synthetically efficient. However, the intrinsic risk of producing the persistent dioxin (“Health Assessment Document for Polychlorinated Dibenzo-p-dioxins”; U.S. Environmental Protection Agency. U. S. Government Printing Office: Washington, DC, 1985; EPA 600/8-84-014F.;“Estimating Exposure to Dioxin-Like Compounds, Vol. I: Executive Summary”, external review draft; Office of Health and Environmental Assessment Office of Research and Development. U.S. Government Printing Office: Washington, DC, June 1994; EPA/600/6-88/005Ca.; “Estimating Exposure to Dioxin-Like Compounds, Vol. II: Properties, Sources, Occurrence and Background Exposures”; external review draft; Office of Health and Environmental Assessment, Office of Research and Development. U.S. Government Printing Office: Washington, DC, June 1994; EPA/60/W6-88/005Cb.) impurities into the final API prompted us to investigate an alternative synthesis route to avoid the involvement of polyhalogenated phenol intermediate such as 3b (Scheme 1)
Optimization of a Class of Dihydrobenzofurane Analogs Toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors
No full textThe inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time
Current Industry Best Practice on In-Use Stability and Compatibility Studies of Biological Products
No full textEvaluating the in-use stability of a biological product including its compatibility with administration components allows to define handling instructions and potential hold times that retain product quality during dose preparation and administration. The intended drug product usage may involve the dilution of drug formulation into admixtures for infusion and exposure to new interfaces of administration components like intravenous (iv) bags, syringes, and tubing. In-use studies assess the potential impact on product quality by simulating drug handling throughout the defined in-use period. Considering the wide range of in-use conditions and administration components available globally, only limited guidance is available from regulators on expected in-use stability data. A working group reviewed and consolidated industry approaches to assess physicochemical stability of traditional protein-based biological products during clinical development and for commercial use. The insights compiled in this review article can be leveraged across the industry and encompass topics such as representative drug product material and administration components, testing conditions, quality attributes evaluated and respective acceptance criteria, applied quality standards, and regulatory requirements. These practices may help companies in the study design, and they may inform discussions with global regulators
Roadmap for exploratory food effect assessment in early clinical development for oncology drugs - literature and Novartis experience
No full textInstructions for administration with regard to food are a key aspect of how patients experience oral drugs. Through potential effects on pharmacokinetics, the food condition can influence safety and efficacy, and thereby is one of many dimensions of dose optimization. Regulatory guidance from major health authorities advocates for the early investigation of food effect (FE) in clinical development. In oncology, exploratory food effect (eFE) evaluation is often incorporated into the first-in-human (FIH) studies in patients to inform food condition of later clinical studies. The design aspects of such exploratory assessments are generally under-reported and barely described, but on the other hand, complex, due to uniqueness of FIH study design and drug development process in oncology. Herein, we provide an outline for setting initial food conditions and review literature of eFE assessments in early phase oncology studies in patients. Further, we reviewed the Novartis experience in the design, execution, and impact of eFE in FIH oncology studies of 2014 - 2021. Based on literature examples and our own experience, we propose a roadmap for eFE assessment in early clinical drug development for oncology drugs, including a framework for common study design options, with a focus on study and patient-level timing for typical scenarios to enable either intra or inter-patient pharmacokinetic comparisons with or without food, as well as a spectrum of decision-making factors spanning from clinical development strategy, FIH study design, to compound specific features, which should be evaluated to drive the design and implementation of eFE assessment
Data sharing for aromatic amines
No full textYearly data sharing on Ames test data for small aromatic amines into the Vitic database. All are small chemicals with CAS numbers. Structure is known in public domain, no Novartis proprietary data disclosed