The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.
Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Andrew A
AA
Wylie
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Joseph
J
Schoepfer
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Wolfgang
W
Jahnke
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Sandra W
SW
Cowan-Jacob
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Alice
A
Loo
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Pascal
P
Furet
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Andreas L
AL
Marzinzik
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Xavier
X
Pelle
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Jerry
J
Donovan
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Wenjing
W
Zhu
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Silvia
S
Buonamici
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
A Quamrul
AQ
Hassan
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Franco
F
Lombardo
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Varsha
V
Iyer
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Michael
M
Palmer
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Giuliano
G
Berellini
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Stephanie
S
Dodd
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Sanjeev
S
Thohan
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Hans
H
Bitter
Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
Susan
S
Branford
Haematology Directorate, SA Pathology, PO Box 14, Rundle Mall, Adelaide, South Australia 5000, Australia.
David M
DM
Ross
South Australian Health &Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
Timothy P
TP
Hughes
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Lilli
L
Petruzzelli
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
K Gary
KG
Vanasse
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Markus
M
Warmuth
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Francesco
F
Hofmann
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Nicholas J
NJ
Keen
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
William R
WR
Sellers
D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects*; D000818:Animals; D020134:Catalytic Domain / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D011720:Pyrazoles; D011743:Pyrimidines; C000621806:asciminib; D009536:Niacinamide; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib