Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile

Abstract

Several small-molecule Bruton tyrosine kinase (BTK) inhibitors are in development for B cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib [compound 1, ACP-196 (4-[8-amino-3-[(2)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-]pyrazin-1-yl]--(2-pyridyl)benzamide)]. Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential. Acalabrutinib demonstrated higher biochemical and cellular selectivity than ibrutinib and spebrutinib (compounds 2 and 3, respectively). Importantly, off-target kinases, such as epidermal growth factor receptor (EGFR) and interleukin 2-inducible T cell kinase (ITK), were not inhibited. Determination of the inhibitory potential of anti-immunoglobulin M-induced CD69 expression in human peripheral blood mononuclear cells and whole blood demonstrated that acalabrutinib is a potent functional BTK inhibitor. In vivo evaluation in mice revealed that acalabrutinib is more potent than ibrutinib and spebrutinib. Preclinical and clinical studies showed that the level and duration of BTK occupancy correlates with in vivo efficacy. Evaluation of the pharmacokinetic properties of acalabrutinib in healthy adult volunteers demonstrated rapid absorption and fast elimination. In these healthy individuals, a single oral dose of 100 mg showed approximately 99% median target coverage at 3 and 12 hours and around 90% at 24 hours in peripheral B cells. In conclusion, acalabrutinib is a BTK inhibitor with key pharmacologic differentiators versus ibrutinib and spebrutinib and is currently being evaluated in clinical trials.

<p>Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data</p>

“…2,17,18 Acalabrutinib, a second generation, irreversible BTK inhibitor, was developed as a selective BTK inhibitor to avoid the off-target side effects seen ibrutinib. [7][8][9] Zanubrutinib, a next-generation, irreversible BTK inhibitor, was developed as a selective BTK inhibitor and has received approval for treatment of relapsed refractory mantle cell lymphoma. 19 Studies are ongoing in evaluating the drug's safety and efficacy in CLL.…”

“…5,6 Acalabrutinib, a second generation and more selective Bruton's tyrosine kinase (BTK) inhibitor, was developed to maximize efficacy while minimizing ibrutinib-associated adverse events hypothesized to be secondary to ibrutinib's off-target effects. [7][8][9] This review will summarize the development, pre-clinical evaluation, and key clinical trials that have demonstrated acalabrutinib's efficacy and toxicity profile in CLL.…”

Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma

“…Bruton tyrosine kinase (BTK) inhibitors have greatly improved the spectrum of treatment options in mantle cell lymphoma (MCL) [1][2][3][4]. Acalabrutinib is a highly selective, orally administered, and potent BTK inhibitor with limited off-target activity [5]. Acalabrutinib was approved in 2017 by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data from the open-label, multicenter, phase 2 ACE-LY-004 study of acalabrutinib 100 mg twice daily [1].…”

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

“…Despite their activity as single agents or in combination, ibrutinib and idelalisib present toxicities (de Weerdt et al , ) that can limit their use in clinical practice and novel compounds are in development to increase the therapeutic window for these classes of agents. Acalabrutinib (ACP‐196) is an irreversible BTK inhibitor with higher selectivity for its target than ibrutinib (Barf et al , ; Herman et al , ). Preclinical anti‐tumour activity in human and mouse models of chronic lymphocytic leukaemia (CLL) (Golay et al , ; Herman et al , ; Patel et al , ) and in a canine diffuse large B‐cell lymphoma (DLBCL) model (Harrington et al , ) have been followed by clinical efficacy data in patients with relapsed CLL or relapsed/refractory mantle cell lymphoma (MCL) with approval by the U.S. FDA (Byrd et al , ; Markham & Dhillon, ; Wang et al , ).…”