Discovery of a novel and highly selective JAK3 inhibitor as a potent hair growth promoter.

Autor: Hossain MM; Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Khalid A; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Akhter Z; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Parveen S; Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Ayaz MO; Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Bhat AQ; Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Badesra N; Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Showket F; Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Dar MS; Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Ahmed F; Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India., Dhiman S; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Kumar M; Medicinal Product Chemistry, Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK., Singh U; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Hussain R; Department of Entomology, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA., Keshari P; Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India., Mustafa G; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Nargorta A; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Taneja N; Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India., Gupta S; Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India., Mir RA; Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India., Kshatri AS; Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India., Nandi U; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Khan N; Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India., Ramajayan P; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Yadav G; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Ahmed Z; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India., Singh PP; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India. ppsingh@iiim.res.in.; Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India. ppsingh@iiim.res.in., Dar MJ; Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India. jamal@iiim.ac.in.; Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India. jamal@iiim.ac.in.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2024 Apr 18; Vol. 22 (1), pp. 370. Date of Electronic Publication: 2024 Apr 18.
DOI: 10.1186/s12967-024-05144-4
Abstrakt: JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC 50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.
(© 2024. The Author(s).)
Databáze: MEDLINE
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