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Ref Type Journal Article
PMID (35820889)
Authors Fang DD, Tao R, Wang G, Li Y, Zhang K, Xu C, Zhai G, Wang Q, Wang J, Tang C, Min P, Xiong D, Chen J, Wang S, Yang D, Zhai Y
Title Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models.
Journal Vol Issue Date Pages Journal Short Title
BMC cancer 22 1 2022 Jul 11 752 BMC Cancer
URL
Abstract Text Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations.KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic-pharmacodynamic correlations and the mechanism of actions driving drug combination synergy.In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449.Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK+ NSCLC refractory to earlier-generation ALK inhibitors.Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
APG-2449 APG-2449 12 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
APG-2449 APG2449|APG 2449 ALK Inhibitor 32 FAK inhibitor 15 ROS1 Inhibitor 20 APG-2449 is a multikinase inhibitor with activity against ALK, ROS1, and FAK, which potentially reduces tumor growth (PMID: 35820889).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK G1202R Advanced Solid Tumor sensitive APG-2449 Preclinical - Cell line xenograft Actionable In a preclinical study, APG-2449 inhibited tumor growth of a cell line xenograft model expressing EML4-ALK with ALK G1202R (PMID: 35820889). 35820889
EML4 - ALK ALK R1275Q Advanced Solid Tumor sensitive APG-2449 Preclinical - Cell culture Actionable In a preclinical study, APG-2449 inhibited proliferation of cells expressing EML4-ALK with ALK R1275Q in culture (PMID: 35820889). 35820889
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive APG-2449 Preclinical - Cell culture Actionable In a preclinical study, APG-2449 inhibited proliferation of a cell line expressing EML4-ALK with ALK F1174L in culture (PMID: 35820889). 35820889
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive APG-2449 Preclinical - Cell line xenograft Actionable In a preclinical study, APG-2449 inhibited tumor growth in a cell line xenograft model expressing EML4-ALK with ALK L1196M (PMID: 35820889). 35820889
ALK G1202R Advanced Solid Tumor predicted - sensitive APG-2449 Preclinical - Biochemical Actionable In a preclinical study, APG-2449 inhibited the kinase activity of ALK G1202R in culture (PMID: 35820889). 35820889
EML4 - ALK ALK I1171T Advanced Solid Tumor sensitive APG-2449 Preclinical - Cell culture Actionable In a preclinical study, APG-2449 inhibited proliferation of cells expressing EML4-ALK with ALK I1171T in culture (PMID: 35820889). 35820889
ALK L1196M Advanced Solid Tumor predicted - sensitive APG-2449 Preclinical - Biochemical Actionable In a preclinical study, APG-2449 inhibited the kinase activity of ALK L1196M in culture (PMID: 35820889). 35820889
EML4 - ALK ALK L1196M Advanced Solid Tumor resistant Crizotinib Preclinical - Cell line xenograft Actionable In a preclinical study, a cell line xenograft model expressing EML4-ALK with ALK L1196M was resistant to Xalkori (crizotinib) (PMID: 35820889). 35820889
EML4 - ALK Advanced Solid Tumor sensitive APG-2449 Preclinical - Cell culture Actionable In a preclinical study, APG-2449 inhibited proliferation of cells expressing EML4-ALK in culture (PMID: 35820889). 35820889
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Zykadia (ceritinib) inhibited tumor growth in a cell line xenograft model expressing EML4-ALK with ALK L1196M (PMID: 35820889). 35820889
EML4 - ALK lung non-small cell carcinoma sensitive APG-2449 Preclinical - Cell line xenograft Actionable In a preclinical study, APG-2449 inhibited proliferation of non-small cell lung cancer cell lines harboring EML4-ALK in culture and resulted in dose-dependent antitumor activity in a cell line xenograft model (PMID: 35820889). 35820889
ALK G1269A Advanced Solid Tumor predicted - sensitive APG-2449 Preclinical - Biochemical Actionable In a preclinical study, APG-2449 inhibited the kinase activity of ALK G1269A in culture (PMID: 35820889). 35820889
EML4 - ALK ALK G1202R Advanced Solid Tumor conflicting Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited tumor growth of a cell line xenograft model expressing EML4-ALK with ALK G1202R (PMID: 35820889). 35820889
ALK S1206Y Advanced Solid Tumor predicted - sensitive APG-2449 Preclinical - Biochemical Actionable In a preclinical study, APG-2449 inhibited the kinase activity of ALK S1206Y in culture (PMID: 35820889). 35820889