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Asciminib: first FDA approved allosteric inhibitor of BCR-ABL1 for the treatment of chronic myeloid leukemia

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Abstract

Chronic myelogenous leukemia (CML), a type of cancer of the white blood cells, arises due to the constitutive activity of the BCR-ABL1 oncoprotein. Several non-specific ATP competitive tyrosine kinase inhibitors including imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) can enhance the overall survival rate of CML patients. However, many of these drugs became resistant due to mutation of the threonine T315 to isoleucine (T315I). Asciminib binds myristate pocket in an allosteric site, outside the catalytic/ATP-binding site. It inhibits both wide- type and mutated T315I BCR-ABL1 activities in vitro, in vivo and in human clinical trials. This very short review discusses the current CML treatment options and mechanism of action, dosage and administration, pharmacokinetic, drug interaction, and side effects of newly approved acciminib.

Graphical Abstract

Asciminib (Scemblix)

Allosteric Inhibitor of BCR-ABL1; Binding to myristate pocket

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Abbreviations

ABL1 :

Abelson proto-oncogene 1

ATP:

adenosine triphosphate

AP:

accelerated phase

AUC:

Area under the curve

BC:

Blast crisis

BCR:

Breakpoint cluster region protein

CML:

Chronic myelogenous leukemia

DCM:

dichloromethane

DIEA:

N,N-diisopropylethylamine

DMF:

N,N-dimethylformamide

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

KD:

Kinase domain

MMR:

Major molecular response

P-gp:

Permeability glycoprotein

Ph+ :

Philadelphia chromosome-positive

i-PrOH:

Isopropyl alcohol

PD:

Pharmacodynamics

PK:

Pharmacokinetic

TFA:

Trifluoroacetic acid

THF:

Tetrahydrofuran

TKIs:

Tyrosine kinase inhibitors

WT:

Wild type

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  1. Conju-probe, San Diego, CA, USA

    Surya K. De

  2. Bharath University, Chennai, Tamil Nadu, 600126, India

    Surya K. De

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De, S.K. Asciminib: first FDA approved allosteric inhibitor of BCR-ABL1 for the treatment of chronic myeloid leukemia. Med Chem Res 32, 424–433 (2023). https://doi.org/10.1007/s00044-022-03011-9

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