Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Angst, Daniela; Gessier, François; Janser, Philipp; Vulpetti, Anna; Wälchli, Rudolf; Berthou, Christian; Littlewood‐Evans, Amanda; Dawson, Janet; Nuesslein‐Hildesheim, Barbara; Wieczorek, Grazyna; Gutmann, Sascha; Scheufler, Clemens; Hinniger, Alexandra; Zimmerlin, Alfred; Funhoff, Enrico G.; Pulz, Robert; Cenni, Bruno

doi:10.1021/acs.jmedchem.9b01916

Cited by 109 publications

(132 citation statements)

References 58 publications

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“…There are a number of in vitro biochemical kinase assays used in the cited reports such as: LanthaScreen (TR-FRET), Z-LYTE and IMAP (FP or TR-FRET). However, these tests have limitations, such as the time-dependent effect during the biochemical determination of the IC50 value for covalent inhibitors (Angst et al, 2020). Furthermore, compound screening using kinase panels and determination of binding constants are used to evaluate the BTKi selectivity ( Table 2).…”

Section: Assaying the Selectivity Of Btkismentioning

confidence: 99%

“…For several of the reviewed BTKis, the reported IC50 data for kinases other than BTK are highly variable, e.g. the acalabrutinib biochemical IC50 values for TEC vary from 37 to 1000 nM (Byrd et al, 2016;Barf et al, 2017;Crawford et al, 2018;Angst et al, 2020;Liclican et al, 2020). Further examples are: spebrutinib inhibition of ITK has been reported as < 40 nM or ≥ 1000 nM (Evans et al, 2013;Byrd et al, 2016;Barf et al, 2017;Crawford et al, 2018;Liclican et al, 2020) and for tirabrutinib, IC50 data presented for RLK/TXK differ by more than 10-fold (Byrd et al, 2016;Crawford et al, 2018;Liclican et al, 2020).…”

Section: Assaying the Selectivity Of Btkismentioning

confidence: 99%

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Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán

Berglöf

Zain

et al. 2021

Front. Cell Dev. Biol.

167

171

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The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.

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Section: Assaying the Selectivity Of Btkismentioning

confidence: 99%

Section: Assaying the Selectivity Of Btkismentioning

confidence: 99%

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán

Berglöf

Zain

et al. 2021

Front. Cell Dev. Biol.

167

171

View full text Add to dashboard Cite

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“…New highly selective reversible or covalent Btk-inhibitors are being developed for the treatment of various autoimmune diseases aiming to inhibit autoantibody-producing B-cells and inflammatory myeloid cells [36,37,38,39]. The reversible Btk-inhibitor fenebrutinib does not inhibit the Btk homologous kinase Tec [37] that is a critical back-up pathway for maintaining physiologic hemostasis under Btk inhibition [14].…”

Section: Dear Sirmentioning

confidence: 99%

Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

2020

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“…Bruton tyrosine kinase (BTK) is a tyrosine kinase expressed in various hematopoietic cells including macrophages, mast cells, and basophils. In addition to playing a major role in B-cell development and functions, BTK is also a part of the FcεR activation and signaling in mast cells [96,97]. BTK inhibitors are used to treat different malignancies of B-cell origin [98].…”

Section: Bruton's Tyrosıne Kınase (Btk) Inhıbıtorsmentioning

confidence: 99%

Targeted Therapy for Chronıc Spontaneous Urtıcarıa: Ratıonale and Recent Progress

Giménez‐Arnau

Salman

2020

Drugs

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Chronic spontaneous urticaria (CSU) is characterized by the presence of wheals, angioedema, or both for at least 6 weeks. It may persist for a long time-up to 50% of the patients have been reported to be symptomatic 5 years after the onset. Some patients can suffer more than one episode of CSU during their lifetime. Considering the recurrences, disabling symptoms, and significant impact on quality of life, proper and effective treatment of CSU is critical. The use of antihistamines (AHs) is still the mainstay of treatment. However, given the low rates of response to AHs (38.6% and 63.2% to standard doses and higher doses, respectively), the complete control of symptoms seems difficult to attain. The use of omalizumab for CSU has been a major breakthrough in the care of patients with CSU. However, the partial response and lack of response to omalizumab in a subgroup of patients, as high as 70% in some studies, make the development of alternative treatments desirable. Ever-increasing knowledge on the pathogenesis is making new target molecules available and enabling drug development for CSU. In addition to drug repurposing as in anti-IL-4/13, IL-5, and IL-17 antibodies, novel targeted therapy options such as ligelizumab and Bruton's tyrosine kinase inhibitors are currently undergoing clinical trials and will be available in the near future. This article reviews the current challenges in the treatment of CSU, the pathogenesis and potential target molecules, and the rationale for novel treatments and their rapidly developing status.

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Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Cited by 109 publications

References 58 publications

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

Targeted Therapy for Chronıc Spontaneous Urtıcarıa: Ratıonale and Recent Progress

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