Janus kinase 1 (JAK1) is a tyrosine kinase that is involved in the initiation of responses to a number of different cytokine receptor families. The JAK1-dependent pathway is a therapeutic target, and several JAK inhibitors have been developed thanks to intensive research. However, since the ATP binding sites of JAK family members are quite alike, JAK1 inhibitors can thus be less selective, resulting in unanticipated adverse effects. Despite this, minor variations in the ATP-binding site have been extensively used to find a variety of small compounds with different inhibitory properties. Stronger binding affinity of JAK1 inhibitors is believed to be able to reduce the negative effects, leading to better treatment results. Therefore, a thorough computational search that can effectively identify ligands with extremely high binding affinity for JAK1 to serve as promising inhibitors is required. Here, a method combining steered-molecular dynamic (SMD) simulations with a modified linear interaction energy (LIE) model has been developed to evaluate the binding affinities of known JAK1 inhibitors. The correlation coefficient between the estimated and experimental values was 0.72 and a root-mean-square error was 0.97 kcal•mol^-1, revealing that the SMD/LIE method can precisely and quickly predict the binding free energies of JAK1 inhibitors. Furthermore, three marine fungus-derived compounds, namely hansforesters E, hansforesters G and tetroazolemycins B, were identified to be particularly promising JAK1 inhibitors, accordingly. These findings show that the SMD/LIE method has a lot of promise for in silico screening of possible JAK1 inhibitors from a vast number of compounds that are now accessible.Communicated by Ramaswamy H. Sarma.

01 Feb 2022·Journal of the European Academy of Dermatology and Venereology

Face atopic dermatitis resistant to dupilumab: a case series of three patients successfully treated with upadacitinib

Letter

Author: Argenziano, G. ; Calabrese, G. ; Licata, G. ; Alfano, R. ; Tancredi, V. ; Gambardella, A. ; De Rosa, A.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease, etiol. is not known but a central role of IL-4 and IL-13 has been discovered.First case is a 26-yr-old man, who came in our department for severe AD, the patient already experienced this therapy with cyclosporine (4 mg/kg) without results, after an informed consent, we prescribed dupilumab, we have continued for 40 wk with high resolution of clinic manifestation when a sudden facial relapse occurred.First, we tried with systemic and topical steroids, but after 6 wk, no benefits were gained, so we switched to upadacitinib, 15 mg by twice day, when patient returned after 1 mo just a mild eczema was visible.Second case is a 38-yr-old woman with AD and other allergic comorbidities, previous treatments include UV-B narrowband phototherapy, systemic steroid and cyclosporine, after 6 wk of dupilumab, improvement was observed, meanwhile the patient developed an itchy eczema on her face and neck which were suspected for to be dupilumab-related regional dermatosis.In addition, in literature, it is reported that dupilumab could worsen or cause facial and periorbital eczema; taking this into account, upadacitinib may be a good option for AD involving the face area.Summing up selective JAK1 inhibitors like upadacitinib could be available for AD for those patients who are not responsive or compliant to dupilumab.

01 Dec 2021·Drug Resistance UpdatesQ1 · MEDICINE

Targeting multidrug resistance-associated protein 1 (MRP1)-expressing cancers: Beyond pharmacological inhibition

Q1 · MEDICINE

Review

Author: Hanssen, Kimberley M ; Haber, Michelle ; Fletcher, Jamie I

Resistance to chemotherapy remains one of the most significant obstacles to successful cancer treatment. While inhibiting drug efflux mediated by ATP-binding cassette (ABC) transporters is a seemingly attractive and logical approach to combat multidrug resistance (MDR), small molecule inhibition of ABC transporters has so far failed to confer clinical benefit, despite considerable efforts by medicinal chemists, biologists, and clinicians. The long-sought treatment to eradicate cancers displaying ABC transporter overexpression may therefore lie within alternative targeting strategies. When aberrantly expressed, the ABC transporter multidrug resistance-associated protein 1 (MRP1, ABCC1) confers MDR, but can also shift cellular redox balance, leaving the cell vulnerable to select agents. Here, we explore the physiological roles of MRP1, the rational for targeting this transporter in cancer, the development of small molecule MRP1 inhibitors, and the most recent developments in alternative therapeutic approaches for targeting cancers with MRP1 overexpression. We discuss approaches that extend beyond simple MRP1 inhibition by exploiting the collateral sensitivity to glutathione depletion and ferroptosis, the rationale for targeting the shared transcriptional regulators of both MRP1 and glutathione biosynthesis, advances in gene silencing, and new molecules that modulate transporter activity to the detriment of the cancer cell. These strategies illustrate promising new approaches to address multidrug resistant disease that extend beyond the simple reversal of MDR and offer exciting routes for further research.

100 Deals associated with AST-NS2102

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Preclinical	China	Shanghai Allist Pharmaceuticals Co., Ltd.	04 Jul 2022
Non-Small Cell Lung Cancer	Preclinical	China	Shanghai Allist Pharmaceuticals Co., Ltd.	04 Jul 2022
Pancreatic Cancer	Preclinical	China	Shanghai Allist Pharmaceuticals Co., Ltd.	04 Jul 2022

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