Introduction
Small-Molecule Protein Kinases Inhibitors
Fungal Infection by Protein Kinase Target
Bruton tyrosine kinase inhibitor
Target | Mechanism of action | Diseases | Drugs |
---|---|---|---|
BTK inhibitor | Interferes with B cell signalling cascades via B cell receptor pathway - Binding to BTK, prevents key phosphorylation - Reduces B Cell differentiation, proliferation and migration - Decreasing B cell survival and anti-tumour activity | Leukaemia (chronic lymphocytic leukaemia) Lymphoma (mantel cell marginal zone) | ImatinibAcalabrutinib |
mTOR inhibitor | Interferes with signalling of growth factors and nutrients via the PI3K/AKT/mTOR protein cascade [64] Acts via mTOR complex 1 - Reduces protein synthesis, glycolysis, lipogenesis leading to autophagy - Reduces angiogenesis, proliferation and migration Acts via mTOR complex 2 - Blocks AKT activation, reducing proliferation & induces cell death (blocks G1/S cell cycle, cell) | Cancer (renal cell carcinoma, breast, pancreas) Renal transplant | Everolimus Temsirolimus Sirolimus |
JAK inhibitor | Interferes with signalling via the JAK-STAT pathway - Signally requires 2 associated JAKs to phosphorylate, - JAK1 pairs with any of the 3 JAKs and signals IFNs, IL-10, IL-6 - JAK2 signals growth hormones (EPO, TPO, GM-CSF) - JAK3 signals γ-chain cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) - TYK signals IFNα & β, IL-12 & IL-23 - Reduces activation of STATs (transcription factors) which would lead to gene transcription [65, 66]. - Decreasing cytokine driven activation and function of both innate and adaptive immune cells | Inflammatory arthritis Myelofibrosis, polycythemia vera | Tofacitinib Baricitinib Ruxolitinib |
BCR-ABL inhibitor | Inhibit ABL tyrosine kinase activity, blocking autophosphorylation driven by the juxtaposition of BCR. - RAS/RAF/MEK/ERK pathway—reducing signalling of nuclear transcription factors which govern cell cycle control & thus decreases cell proliferation - JAK-STAT pathway—impairing transcriptional activity via cytokine & hormone signalling - PI3K/AKT/mTOR pathway—resulting in increased apoptosis | Haematological malignancies (Philadelphia chromosome–positive chronic myeloid leukaemia, myelodysplastic syndromes, myeloproliferative disorder) | Imatinib Dasatinib Nilotinib PonatinibBosutinib |
Therapeutic targets | Indication | Drugs | Year | Fungal infect. | Data source | Subtypes of fungal infection |
---|---|---|---|---|---|---|
BCR-ABL | Haematological malignancies | Imatinib (Gleevec) | 2001 | 5 | Case reports | |
Dasatinib (Sprycell) | 2006 | 13 | Analysis Safety Data (n = 165) | |||
Retrospective analysis* (n = 69) Retrospective analysis* (n = 16) | ||||||
Case reports | PJP (n = 2) [58] | |||||
Nilotinib (Tasigna) | 2007 | 1 | Retrospective analysis* (n = 169) | Unspecified fungal (n = 1) [69] | ||
Ponatinib (Iclusig) | 2012 | 1 | Retrospective analysis* (n = 15) | Unspecified fungal (n = 1) [70] | ||
Bosutinib (Bosulif) | 2012 | 1 | Case reports | Aspergillosis pulmonary (n = 1) [55] | ||
BTK | Haematological malignancies | Ibrutinib (Imbruvica) | 2013 | 269 | Retrospective analysis database (n = unknown) | |
Retrospective multicentre (n = 235) | Unspecified fungal (n = 11) [71] | |||||
Retrospective multicentre | Aspergillosis (n = 18), cryptococcosis (n = 7), PJP (n = 1), mucormycosis (n = 3), combined fungal (n = 1) [21] | |||||
Retrospective database | Aspergillosis invasive (n = 5) [72] | |||||
Retrospective analysis* (n = 556) | ||||||
Retrospective analysis* (n = 200) | ||||||
Retrospective analysis* (n = 68) | Aspergillosis invasive (n = 2), cryptococcal disseminated (n = 1), mucormycosis (n = 1), PJP (n = 1) [74] | |||||
Retrospective analysis* (n = 37) | ||||||
Systematic review literature | Aspergillosis CNS, lung, cavernous sinus (n = 18), cryptococcosis CNS, lung, skin, blood (n = 7), histoplasmosis (n = 1), Fusarium solani (i = 1), mucormycosis (n = 1), PJP (n = 7), zygomycota (n = 1) [19] | |||||
Systematic review literature | Aspergillosis (n = 71) [11] | |||||
Systematic review literature | ||||||
Case reports | Aspergillosis CNS (n = 3) [11,77,78], pulmonary (n = 1) [79], myocardial (n = 1) [80], cryptococcosis disseminated (n = 2) [81,82], CNS (n = 4) [20,83,84], pneumonia (n = 1) [83], empyema (n = 2) [19,85], Candida pneumonia (n = 2) [86,87], mucormycosis invasive (n = 1) [86], abdominal (n = 1) [84], sinus (n = 1) [88] skin (n = 2) [89,90], PJP (n = 5) [25] | |||||
Acalabrutinib (Calquence) | 2017 | 5 | Analysis safety data (n = 601) | |||
Case reports | Cryptococcal disseminated (n = 1) [27] | |||||
JAK/STAT | Polycythaemia vera inflammatory arthritis | Ruxolitinib (Jakafi) | 2011 | 23•• | Retrospective analysis database | Aspergillosis pulmonary (n = 1), cryptococcus pulmonary (n = 1), mucormycosis pulmonary (n = 1), PJP (n = 1) [91] |
Retrospective multicentre (n = 446) | Aspergillosis disseminated (n = 1), candida oesophageal (n = 1), intestinal (n = 1), onychomycosis (n = 1) [92] | |||||
Retrospective analysis* (n = 11) | Unspecified fungal oesophagitis (n = 1) [93] | |||||
Systematic review literature | Cryptococcosis CNS, pulmonary, disseminated (n = 3), PJP (n = 2), mucormycosis (n = 1), talaromycosis disseminated (n = 1) [42] | |||||
Case reports | ||||||
Tofacitinib (Xeljanz) | 2012 | 37 | Safety data (34,223 patient-years) | Cryptococcosis pneumonia (n = 3), Candida oesophageal (n = 2), orpharyngeal (n = 2), histoplasmosis (n = 2), PJP (n = 1) [44] | ||
RCT and LTE studies (n = 5671) | Cryptococcosis pneumonia (n = 2), CNS (n = 1), candida oesophageal (n = 9), PJP (n = 4), toxoplasmosis (n = 1) [45] | |||||
LTE studies (n = 4967) | ||||||
Retrospective analysis* | Histoplasmosis (n = 1) [101] | |||||
Baricitinib (Olumiant) | 2012 | 15 | RCT and LTE studies (n = 3492) | Aspergillosis skin (n = 1), cryptococcal pneumonia (n = 1), candida oesophageal (n = 6), lung (n = 1), soft tissue (n = 1), histoplasmosis (n = 1) PJP (n = 3), PCM (n = 1) [45] | ||
mTOR | Transplant Solid organ cancer (breast, pancreas, renal) | Sirolimus (Rapamycin) | 1999 | 66 | RCT (n = 124) | Cryptococcal CNS mortality (n = 1), unspecified fungal disseminated mortality (n = 1), PJP (n = 7, of which 3 died) [33] |
Retrospective database (n = 4898) | PJP (n = 41) [32••] | |||||
Retrospective analysis* (n = 79) | ||||||
Retrospective analysis* (n = 49) | Unspecified fungal (n = 9) [103] | |||||
Retrospective analysis* (n = 33) | Unspecified fungal (n = 2) [104] | |||||
Retrospective analysis* (n = 20) | PJP (n = 2) [105] | |||||
Case reports | Fusarium (n = 2) [106] | |||||
Temsirolimus (Torisel) | 2007 | 11 | Meta-analysis# (n = 1601) | |||
Case reports | ||||||
Everolimus (Afinitor) | 2009 | 21 | Meta-analysis# (n = 1601) | |||
Retrospective analysis* (n = 12) | PJP (n = 6) [35] | |||||
Retrospective analysis* (n = 7) | Candida oesophageal (n = 1) [109] | |||||
Case reports | ||||||
VEGFR | Solid organ cancer (hepatic, thyroid, renal, pancreatic, CRC) | Sorafenib (Nexavar) | 2005 | 3 | Case reports | |
Sunitinib (Sutent) | 2006 | 2 | Case reports | |||
EGFR | Solid organ cancer (NSCLC, pancreas, breast) | Gefitinib (Iressa) | 2003 | 1 | Case reports | Aspergillosis invasive (n = 1) [117] |
ALK | NSCLC | Crizotinib (Xalkori) | 2011 | 1 | Case reports | Aspergillosis invasive (n = 1) [118] |