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

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

  • J Transl Med. 2024 Apr 18;22(1):370. doi: 10.1186/s12967-024-05144-4.
Md Mehedi Hossain # 1 2,  Arfan Khalid # 2 3,  Zaheen Akhter # 2 4,  Sabra Parveen 1 2,  Mir Owais Ayaz 1 2,  Aadil Qadir Bhat 1 2,  Neetu Badesra 1 2,  Farheen Showket 1 2,  Mohmmad Saleem Dar 1 2,  Farhan Ahmed 5,  Sumit Dhiman 2 3,  Mukesh Kumar 6,  Umed Singh 2 4,  Razak Hussain 7,  Pankaj Keshari 8,  Ghulam Mustafa 2 3,  Amit Nargorta 2 4,  Neha Taneja 9,  Somesh Gupta 9,  Riyaz A Mir 8,  Aravind Singh Kshatri 5,  Utpal Nandi 2 3,  Nooruddin Khan 10,  P Ramajayan 2 3,  Govind Yadav 2 3,  Zabeer Ahmed 2 3,  Parvinder Pal Singh 11 12,  Mohd Jamal Dar 13 14
Affiliations

Affiliations

  • 1 Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.
  • 2 Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.
  • 3 Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.
  • 4 Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India.
  • 5 Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India.
  • 6 Medicinal Product Chemistry, Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
  • 7 Department of Entomology, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA.
  • 8 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
  • 9 Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India.
  • 10 Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India.
  • 11 Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India. ppsingh@iiim.res.in.
  • 12 Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India. ppsingh@iiim.res.in.
  • 13 Laboratory of Cell and Molecular Biology, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India. jamal@iiim.ac.in.
  • 14 Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India. jamal@iiim.ac.in.
  • # Contributed equally.
PMID: 38637842 DOI: 10.1186/s12967-024-05144-4
Abstract

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 IC50 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.

Keywords

3-pyrimidinylazaindole; Alopecia areata; Baricitinib; Hair follicles; JAK-STAT signalling; Ritlecitinib; Tofacitinib.

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