Acalabrutinib [(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide]
is a novel, second generation, irreversible Bruton's tyrosine kinase (BTK)
inhibitor that may show advantages in terms of binding specificity and
drug-drug interactions compared to the first generation BTK inhibitor. It is
being developed by Acerta Pharma BV for treatment of Chronic Lymphocytic
Leukemia (CLL). The improved selectivity and target coverage
of Acalabrutinib has been credited to its covalent bonding with a cysteine
residue (Cys481) in the front position of the ATP-binding pocket [1,2].
Targeting Bruton's tyrosine kinase (BTK), an essential kinase in the B cell receptor (BCR) pathway in patients with chronic lymphocytic leukemia (CLL) has proven very effective. For the first generation BTK inhibitor Ibrutinib, clinical response rates greater than 70% and 75% and progression free survival greater than 2 years have been reported for previously treated patients. Survival and proliferation of CLL cells is highly dependent on microenvironment interaction, which must be taken into consideration when testing new drugs for CLL.
The activity of Acalabrutinib is as follows:
EC50 (BTK enzyme activity) = less than 10 nM
EC50 (LCK enzyme activity) = greater than 1 uM
EC50 (SRC enzyme activity) = greater than 1 uM
EC50 (FYN enzyme activity) = greater than 1 uM
EC50 (LYN enzyme activity) = greater than 1 uM
Acalabrutinib: 2D and 3D Structure |
Targeting Bruton's tyrosine kinase (BTK), an essential kinase in the B cell receptor (BCR) pathway in patients with chronic lymphocytic leukemia (CLL) has proven very effective. For the first generation BTK inhibitor Ibrutinib, clinical response rates greater than 70% and 75% and progression free survival greater than 2 years have been reported for previously treated patients. Survival and proliferation of CLL cells is highly dependent on microenvironment interaction, which must be taken into consideration when testing new drugs for CLL.
The activity of Acalabrutinib is as follows:
EC50 (BTK enzyme activity) = less than 10 nM
EC50 (LCK enzyme activity) = greater than 1 uM
EC50 (SRC enzyme activity) = greater than 1 uM
EC50 (FYN enzyme activity) = greater than 1 uM
EC50 (LYN enzyme activity) = greater than 1 uM
Common Name: Acalabrutinib
Synonyms: ACP-196; ACP 196; ACP196
IUPAC Name: (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide
CAS Number: 1420477-60-6
SMILES:O=C(NC1=NC=CC=C1)C2=CC=C(C3=C4C(N)=NC=CN4C([C@H]5N(C(C#CC)=O)CCC5)=N3)C=C2
Mechanism of Action: Kinase Inhibitor; BTK Inhibitor
Indication: Chronic Lymphocytic Leukemia
Development Stage: Phase II
Company: Acerta Pharma BV
EP2734522A1: First reported synthesis.
Synonyms: ACP-196; ACP 196; ACP196
IUPAC Name: (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide
CAS Number: 1420477-60-6
SMILES:O=C(NC1=NC=CC=C1)C2=CC=C(C3=C4C(N)=NC=CN4C([C@H]5N(C(C#CC)=O)CCC5)=N3)C=C2
Mechanism of Action: Kinase Inhibitor; BTK Inhibitor
Indication: Chronic Lymphocytic Leukemia
Development Stage: Phase II
Company: Acerta Pharma BV
Acalabrutinib Synthesis
EP2734522A1: First reported synthesis.
Bruton's tyrosine kinase (Btk) is
a nonreceptor enzyme in the Tec kinase family expressed among cells of
hematopoietic origin including B cells, myeloid cells, mast cells and
platelets, but not T cells, where it regulates multiple cellular processes.
ACP-196 shows in vivo efficacy
against human chronic lymphocytic leukemia cells xenografted to the NSG mouse
model. Peripheral blood mononuclear cells from previously untreated CLL
patients were injected intravenously into NSG mice. Mice received ACP-196 through
the drinking water. The effect of ACP-196 on xenografted CLL cells from
peripheral blood and spleen was assessed by flow cytometry. At all dose
levels tested, ACP-196 significantly inhibited proliferation of human CLL cells
in the spleens of NSG mice. As seen with other BCR inhibitors, ACP-196
transiently increased CLL cell counts in the peripheral blood in a dose
dependent manner (p = 0.01). ACP-196 inhibited BCR signaling in vivo, as
demonstrated by reduced phosphorylation of PLCy2 [1].
ACP-196 demonstrated higher
selectivity for Btk when profiled against a panel of 395 non-mutant kinases (greater than 1
µM) in a competitive binding assay. IC50 determinations on 9 kinases with a Cys
in the same position as Btk showed ACP-196 to be the most selective. The
improved selectivity is related to the reduced intrinsic reactivity of
ACP-196’s electrophile. Importantly, unlike ibrutinib, ACP-196 did not inhibit
EGFR, ITK or TXK. Phosphoflow assays on EGFR expressing cell lines confirmed
ibrutinib’s EGFR inhibition (EC50 =
47-66 nM) with no inhibition observed for ACP-196 at 10 µM. These data may
explain the Ibrutinib-related incidence of diarrhea and rash [3].
For Canine Lovers
ACP-196 has been tested in normal
dogs and was found to be safe at doses to be used in this clinical trial. Given
the demonstrated activity of ibrutinib in dogs with B cell lymphoma, it is
expected that ACP-196 will show good activity in this setting as well.
Identifications:
Identifications:
1H NMR (Estimated) for Acalabrutinib |
References:
1. Niemann, C. U.; et. al. Abstract 2624: The novel Bruton's tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model. Cancer Res 2014, 74, 2624.
2. Lannutti, B. J.; et. al. Abstract 408: ACP-196, an orally bioavailable covalent selective inhibitor of Btk, modulates the innate tumor microenvironment, exhibits antitumor efficacy and enhances gemcitabine activity in pancreatic cancer. Cancer Res 2015, 75, 408.
3. Covey, T.; et. al. Abstract 2596: ACP-196: a novel covalent Bruton's tyrosine kinase (Btk) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) patients. Cancer Res 2015, 75, 2596.
4. ClinicalTrials.gov ACP-196, a Novel Bruton Tyrosine Kinase (Btk) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia. NCT02029443 (retrieved on 20-04-2015)
5. ClinicalTrials.gov An Open-label, Phase 1b Study of ACP 196 in Subjects With Waldenström Macroglobulinemia. NCT02180724 (retrieved on 20-04-2015)
6. Barf, T. A.; et. al. 4-imidazopyridazin-1-yl-benzamides and 4- imidazotriazin-1-yl-benzamides as btk-inhibitors. EP2734522A1
1. Niemann, C. U.; et. al. Abstract 2624: The novel Bruton's tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model. Cancer Res 2014, 74, 2624.
2. Lannutti, B. J.; et. al. Abstract 408: ACP-196, an orally bioavailable covalent selective inhibitor of Btk, modulates the innate tumor microenvironment, exhibits antitumor efficacy and enhances gemcitabine activity in pancreatic cancer. Cancer Res 2015, 75, 408.
3. Covey, T.; et. al. Abstract 2596: ACP-196: a novel covalent Bruton's tyrosine kinase (Btk) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) patients. Cancer Res 2015, 75, 2596.
4. ClinicalTrials.gov ACP-196, a Novel Bruton Tyrosine Kinase (Btk) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia. NCT02029443 (retrieved on 20-04-2015)
5. ClinicalTrials.gov An Open-label, Phase 1b Study of ACP 196 in Subjects With Waldenström Macroglobulinemia. NCT02180724 (retrieved on 20-04-2015)
6. Barf, T. A.; et. al. 4-imidazopyridazin-1-yl-benzamides and 4- imidazotriazin-1-yl-benzamides as btk-inhibitors. EP2734522A1