Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors

Abstract

BackgroundImatinib shows limited efficacy in patients with gastrointestinal stromal tumors (GISTs) carrying secondary KIT mutations. HQP1351, an orally bioavailable multikinase BCR-ABL inhibitor, is currently in clinical trials for the treatment of T315I mutant chronic myelogenous leukemia (CML), but the potential application in imatinib-resistant GISTs carrying secondary KIT mutations has not been explored.MethodsThe binding activities of HQP1351 with native or mutant KIT were first analyzed. Imatinib-sensitive GIST T1 and imatinib-resistant GIST 430 cells were employed to test the in vitro antiproliferative activity. Colony formation assay, cell migration assay and cell invasion assay were performed to evaluate the clonogenic, migration and invasion ability respectively. Flow cytometry and western blot analysis were used to detect cell apoptosis, cell cycle and signaling pathway. In vivo antitumor activity was evaluated in mouse xenograft models derived from GIST cell lines.ResultsHQP1351 potently inhibited both wild-type and mutant KIT kinases. In both imatinib-resistant and sensitive GIST cell lines, HQP1351 exhibited more potent or equivalent antiproliferative activity compared with ponatinib, a third generation BCR-ABL and KIT inhibitor. HQP1351 led to more profound inhibition of cell colony formation, cell migration and invasion, cell cycle arrest and cell apoptosis than ponatinib. Furthermore, HQP1351 also inhibited p-KIT, p-AKT, p-ERK1/2, and p-STAT3 to a higher extent than ponatinib. Finally, in xenograft tumor models derived from imatinib-resistant GIST cancer cell lines, HQP1351 exhibited antitumor activity superior to ponatinib.ConclusionsCollectively, our in vitro and in vivo results suggest that the therapeutic application of HQP1351 in imatinib-resistant GIST patients deserves further investigation in clinical trials.

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

“…Other new molecules are already under clinical trials e.g., PF-114, HQP1351 (Olverembatinib), and K0706 (Vodobatinib), which function competitively as inhibitors of BCR-ABL1 TK at the ATP-binding site ( Table 2 ) [ 249 ]. These inhibitors have presented an increased potency against a wide range of BCR-ABL1 mutations [ 249 , 250 , 251 , 252 ] and may overcome some the limitations of approved TKIs. Unlike other TKIs, Olverembatinib is able to bind to the kinase in the presence of T315I mutations since it does not form the hydrogen bond with the hydroxyl group at this residue [ 251 ].…”

“…These inhibitors have presented an increased potency against a wide range of BCR-ABL1 mutations [ 249 , 250 , 251 , 252 ] and may overcome some the limitations of approved TKIs. Unlike other TKIs, Olverembatinib is able to bind to the kinase in the presence of T315I mutations since it does not form the hydrogen bond with the hydroxyl group at this residue [ 251 ]. On the contrary, PF-114 is structurally very similar to Ponatinib but modified to avoid the VEGFR inhibition associated with cardiovascular side effects [ 252 ].…”

Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review

“…The results showed a complete hematologic response in 95% of individuals. Moreover, 69% of participants had a major cytogenetic response, 61% had a CCyR, and 37% had a MMR during a follow-up of 12 mo[ 138 ].…”

FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

“…It is currently under investigation in multiple clinical trials for chronic myeloid leukemia (CML; NCT04260022; NCT03883087; NCT04126681; NCT03883100). As a multikinase inhibitor, HQP1351 has also demonstrated potent inhibition on FLT3, fibroblast growth factor receptor, KIT and several other oncogenic kinases [29] , [30] , [31] . Lisaftoclax (APG-2575), a novel selective BCL-2 inhibitor developed by Ascentage Pharma [32] , is currently being tested clinically for several hematologic malignancies, including relapsed/refractory AML (NCT04215809, NCT04494503, NCT04501120).…”