Properties of FDA-approved small molecule protein kinase inhibitors: A 2024 update

Pharmacological Research, Journal Year: 2024, Volume and Issue: 200, P. 107059 - 107059

Published: Jan. 11, 2024

Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one most important drug targets 21st century. There are 80 FDA-approved therapeutic agents that target about two dozen different kinases and seven these drugs were approved 2023. Of drugs, thirteen protein-serine/threonine kinases, four directed against dual specificity (MEK1/2), twenty block nonreceptor protein-tyrosine 43 inhibit receptor kinases. The data indicate 69 prescribed for treatment neoplasms. Six (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) used inflammatory (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, ulcerative colitis). nearly multiple diseases. following received FDA approval 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung ritlecitinib (alopecia areata). All orally effective with exception netarsudil, temsirolimus, trilaciclib. This review summarizes physicochemical properties all molecule inhibitors molecular weight, number hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, ligand efficiency.

Language: Английский

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Pathogenesis of Alopecia Areata and Vitiligo: Commonalities and Differences

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4409 - 4409

Published: April 17, 2024

Both alopecia areata (AA) and vitiligo are distinct, heterogenous, complex disease entities, characterized by nonscarring scalp terminal hair loss skin pigment loss, respectively. In AA, inflammatory cell infiltrates in the deep reticular dermis close to bulb (swarm of bees), whereas epidermis papillary dermis. Immune privilege collapse has been extensively investigated AA pathogenesis, including suppression immunomodulatory factors (e.g., transforming growth factor-β (TGF-β), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), macrophage migration inhibitory factor (MIF)) enhanced expression major histocompatibility (MHC) throughout follicles. However, immune remains less explored. autoimmune diseases that share commonalities involvement plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) cytotoxic CD8+ T lymphocytes activated IFN-γ pathways). Blood chemokine C-X-C motif ligand 9 (CXCL9) CXCL10 elevated both diseases. Common contribute include oxidative stress, autophagy, type 2 cytokines, Wnt/β-catenin pathway dickkopf (DKK1)). Here, we summarize differences between vitiligo, focusing on their pathogenesis.

Language: Английский

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Deciphering the Complex Immunopathogenesis of Alopecia Areata

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 5652 - 5652

Published: May 22, 2024

Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results non-scarring partial to total scalp or body loss. Despite growing knowledge about AA, its exact cause still needs be understood. However, immunity and genetic factors are affirmed critical AA development. While genome-wide association studies proved innate acquired involvement, mouse models implicated IFN-γ- cytotoxic CD8+ T-cell-mediated immune response as main drivers of disease pathogenesis. The loss caused by inflammation HF area, disturbing function disrupting growth cycle without destroying follicle. Thus, privilege, autoimmune destruction mediated mechanisms, upregulation inflammatory pathways play a crucial role. associated with concurrent systemic disorders such atopic dermatitis, vitiligo, psoriasis, thyroiditis. Likewise, patient’s quality life (QoL) significantly impaired morphologic disfigurement illness. patients experience negative impact on psychological well-being self-esteem may more likely suffer from psychiatric comorbidities. This manuscript aims present latest pathogenesis involves genetic, epigenetic, immunological, environmental factors, particular emphasis immunopathogenesis.

Language: Английский

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Efficacy, safety and tolerability of drugs for alopecia: a comprehensive review

Expert Opinion on Drug Metabolism & Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Alopecia, encompassing non-scarring and scarring types, presents therapeutic challenges requiring individualized approaches based on pathophysiology treatment responses. A comprehensive literature search of PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web Science (2015-2024) focused randomized controlled trials, meta-analyses, observational studies. This review evaluates pharmacological strategies for androgenetic alopecia (AGA), areata (AA), alopecias, emphasizing efficacy safety. Treatments include finasteride, minoxidil, JAK inhibitors, antiandrogens like spironolactone. such as baricitinib, show promise AA but require monitoring due to immune suppression risks. Scarring including lichen planopilaris discoid lupus erythematosus, are managed with systemic agents hydroxychloroquine corticosteroids, alongside adjunctive topical laser therapies. The future is poised transformation, particularly AGA. Emerging targeted therapies, inhibitors AA, represent significant advancements. Additionally, innovations in regenerative medicine delivery systems AGA treatments, nanotechnology 3D bioprinting, enhanced personalization. shift toward mechanism-targeted therapy expected improve outcomes various subtypes.

Language: Английский

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Pathophysiology of Alopecia Areata in the Pediatric Patient

Pediatric Dermatology, Journal Year: 2025, Volume and Issue: 42(S1), P. 24 - 30

Published: March 1, 2025

Alopecia areata (AA) is an autoimmune non-scarring hair loss that arises in genetically susceptible individuals, potentially combination with environmental triggers or inciting events, of which the exact mechanism not yet fully understood. Genome wide association studies have demonstrated between AA and variants HLA haplotypes on chromosome 6 correlate other conditions as well gene variants. Familial twin also confer additional evidence to a genetic component. pathogenesis relies immune privilege collapse at follicle (HF) bulb anagen cycle phase. Immune associated upregulation IFN-γ, ultimately activating JAK-STAT pathway resulting MHC class I II HF subjecting it attack by NKG2D+ CD8 T cells. The complex interplay pro-inflammatory cytokines such IL-2, IL-15 their use signaling are important perpetuation AA.

Language: Английский

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Efficacy and safety of the oral JAK3/TEC family kinase inhibitor ritlecitinib over 24 months: integrated analysis of the ALLEGRO phase 2b/3 and long-term phase 3 clinical studies in alopecia areata

British Journal of Dermatology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 21, 2024

Abstract Background The ALLEGRO phase IIa and IIb/III (NCT02974868 NCT03732807) studies have demonstrated that ritlecitinib is effective well tolerated in adults adolescents with alopecia areata (AA) up to 48 weeks. Objectives To assess the efficacy of through month 24 safety data cutoff study ongoing long-term open-label III ALLEGRO-LT (NCT04006457). Methods Patients aged ≥ 12 years AA 50% scalp hair loss from who rolled over after weeks were included. Proportions patients responses based on clinician-reported Severity Alopecia Tool (SALT) scores ≤ 20 10, eyebrow assessment (EBA) eyelash (ELA), patient global impression change (PGI-C) satisfaction growth reported for received 50 mg daily or without a 200-mg 4-week loading dose. Observed imputed [last observation carried forward (LOCF)] 9 December 2022. Safety was assessed throughout. Results At 12, SALT score achieved by 45.1% 45.9% (observed) 40.3% 41.8% (LOCF) 191 194 200 mg/50 mg, respectively. 24, these proportions increased 60.8% 63.1% 46.1% 50.8% (LOCF), abnormal EBA ELA at baseline [EBA observed: 57.6% (50 mg), 61.0% (200/50 mg); LOCF: 46.8% 50.9% 51.2% 62.7% 43.2% 51.7% mg)]. PGI-C response [observed: 70.0% 76.4% 56.6% 65.5% profiles both treatment groups consistent known profile ritlecitinib. Conclusions Ritlecitinib has clinically meaningful sustained beyond 1 year favourable tolerability profile, supporting its use AA.

Language: Английский

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Baricitinib-Induced Remission of Alopecia Universalis in a Child with NFKB2-Associated Immune Dysregulation

Journal of Clinical Immunology, Journal Year: 2025, Volume and Issue: 45(1)

Published: Jan. 2, 2025

Language: Английский

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Modern Management Approaches for Alopecia Areata

Вопросы современной педиатрии, Journal Year: 2025, Volume and Issue: 23(6), P. 516 - 522

Published: Jan. 6, 2025

Alopecia areata is a chronic genetically determined inflammatory autoimmune disease damaging hair follicles and leading to temporary or persistent nonscarring loss. Janus kinase inhibitors have been registered for its management, it allows personalize the therapy increase efficacy by relieving symptoms positively affecting patients’ quality of life. This group drugs considered as basic one treatment alopecia severe forms. The issue relapses after cessation safety long-term with such are covered.

Language: Английский

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Dual improvement of alopecia areata and immune thrombocytopenia with baricitinib: a case report

Skin Health and Disease, Journal Year: 2025, Volume and Issue: 5(1), P. 66 - 69

Published: Jan. 22, 2025

Abstract The oral Janus kinase (JAK) inhibitor baricitinib is approved by the U.S. Food and Drug Administration for treatment of alopecia areata (AA). We report a case dual improvement AA immune thrombocytopenia (ITP) with monotherapy, which may suggest linked autoimmune pathophysiology. In phase III clinical trials AA, reports rare adverse haematological events include neutropenia anaemia. While history comorbidities raise concern many clinicians when considering JAK inhibitor, this vignette suggests that be considered safely administered in those concomitant ITP. A 56-year-old man ITP vitiligo presented to clinic relapse his steroid-resistant hair loss had previously been treated tofacitinib. consultation patient’s haematologist, 2 mg daily was started close platelet monitoring then doubled 4 after platelets showed at 6-month follow-up. Fourteen months initiating baricitinib, white dark regrowth observed, remained normal. Thus, regular co-management haematology colleagues.

Language: Английский

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Patterns of clinical response in patients with alopecia areata treated with ritlecitinib in the ALLEGRO clinical development programme

Journal of the European Academy of Dermatology and Venereology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Background Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, demonstrated efficacy over 48 weeks in patients with alopecia areata (AA) the ALLEGRO phase 2b/3 study. Objectives This post hoc analysis evaluated individual Severity of Alopecia Tool (SALT) score trajectories who received ritlecitinib 50 mg and rolled from Phase into ongoing, open‐label, 3 ALLEGRO‐LT study to describe long‐term response patterns associated baseline disease characteristics. Methods Patients aged ≥12 years ≥50% scalp hair loss once daily both studies. SALT Month 24 were used categorise as early (SALT ≤20 at Week Months 12 24), middle (≤20 24) or late responders by partial (maintained 30% improvement), relapsers (achieved but did not maintain improvement) non‐responders (did achieve improvement). The proportions achieving sustained maintained all subsequent available time points through complete 0 ≥1 point evaluated. Multivariable logistic regression assessed variables response. Results Of 191 treated mg, 87 (45.5%) ≤20), (12.6%) responders, 56 (29.3%) non‐responders. categorised 81 (93.1%) their clinical 47 (46.0%) achieved Factors treatment included female sex less extensive shorter duration loss. Conclusions Approximately 45% up 11% requiring >1 year response, highlighting importance extended duration. ClinicalTrials.gov Registration (NCT03732807); (NCT04006457).

Language: Английский

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