The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase.

Asciminib is a potent, orally bioavailable, investigational drug that specifically and potently inhibits the tyrosine kinase activity of native ABL1, together with that of the chimeric BCR-ABL1 oncoprotein which causes chronic myeloid leukemia (CML). In contrast to ATP-competitive BCR-ABL1 kinase inhibitors employed to treat CML that target multiple kinases, asciminib binds to the myristate binding pocket on the kinase domains of ABL1 and BCR-ABL1. Hitherto no drugs have been developed whose mechanism of action involves interacting with myristate binding pockets on proteins, and analysis of the structures of such binding sites in proteins other than ABL1/ABL2/BCR-ABL1 strongly suggest that asciminib will not bind to these with high affinity. Accordingly, the drug has no known safety liabilities resulting from any off-target activity, as illustrated by its specificity towards cells expressing BCR-ABL1 and lack of effects on non-kinase targets in biochemical screens. Because asciminib does not bind to the ATP-binding site it maintains substantial activity against kinase domain mutations that impart acquired drug resistance to ATP-competitive drugs. However, in vitro studies in cells have identified BCR-ABL1 mutations that reduce the anti-proliferative activity of asciminib, some of which are associated with clinical resistance towards the drug in patients. Here we review effects of asciminib on mutant forms of BCR-ABL1, analyse their sensitivity towards the drug from a structural perspective and affirm support for employing combinations with ATP-competitive inhibitors to impede the reactivation of BCR-ABL1 kinase activity in patients receiving monotherapy.

Manley PW ，Barys L ，Cowan-Jacob SW 《-》

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1.

Schoepfer J ，Jahnke W ，Berellini G ，Buonamici S ，Cotesta S ，Cowan-Jacob SW ，Dodd S ，Drueckes P ，Fabbro D ，Gabriel T ，Groell JM ，Grotzfeld RM ，Hassan AQ ，Henry C ，Iyer V ，Jones D ，Lombardo F ，Loo A ，Manley PW ，Pellé X ，Rummel G ，Salem B ，Warmuth M ，Wylie AA ，Zoller T ，Marzinzik AL ，Furet P ... -  《-》

Development of asciminib, a novel allosteric inhibitor of BCR-ABL1.

Chronic myeloid leukemia (CML) is driven by a translocation event between chromosomes 9 and 22, leading to the formation of a constitutively active BCR-ABL1 oncoprotein. Approved tyrosine kinase inhibitors (TKIs) for CML inhibit BCR-ABL1 by competitively targeting its adenosine triphosphate (ATP)-binding site, which significantly improves patient outcomes. However, resistance to and intolerance of TKIs remains a clinical challenge. Asciminib is a promising investigational agent in development that allosterically targets BCR-ABL1 in a non-ATP-competitive manner. It binds to the ABL1 myristoyl-binding pocket and is effective against most ABL1 kinase domain mutations that confer resistance to ATP-competitive TKIs, including the T315I mutation. This review discusses unmet needs in the current CML treatment landscape, reports clinical data from asciminib trials that support the use of single-agent asciminib as third-line therapy and beyond, and explores the potential benefit of asciminib in combination with approved TKIs in earlier lines.

Réa D ，Hughes TP 《-》

Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants.

BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1T315I-mutant disease. However, therapy options are limited for patients with leukemic clones bearing multiple BCR-ABL1 mutations. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, is active against most single mutants but ineffective against all tested compound mutants. We demonstrate that combining asciminib with ATP site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph+ clinical isolates and cell lines. Inclusion of asciminib restores ponatinib's effectiveness against currently untreatable compound mutants at clinically achievable concentrations. Our findings support combining asciminib with ponatinib as a treatment strategy for this molecularly defined group of patients.

Eide CA ，Zabriskie MS ，Savage Stevens SL ，Antelope O ，Vellore NA ，Than H ，Schultz AR ，Clair P ，Bowler AD ，Pomicter AD ，Yan D ，Senina AV ，Qiang W ，Kelley TW ，Szankasi P ，Heinrich MC ，Tyner JW ，Rea D ，Cayuela JM ，Kim DW ，Tognon CE ，O'Hare T ，Druker BJ ，Deininger MW ... -  《-》

BCR::ABL1 kinase N-lobe mutants confer moderate to high degrees of resistance to asciminib.

Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia. The first 5 approved BCR::ABL1 TKIs target the adenosine triphosphate (ATP)-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non-ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here, we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamic simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the α-C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.

Leyte-Vidal A ，Garrido Ruiz D ，DeFilippis R ，Leske IB ，Rea D ，Phan S ，Miller KB ，Hu F ，Mase A ，Shan Y ，Hantschel O ，Jacobson MP ，Shah NP ... -  《-》