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DRUG:

APG-2449

i
Other names: APG-2449, APG 2449
Company:
Ascentage Pharma
Drug class:
ALK inhibitor, Multi-tyrosine kinase inhibitor, ROS1 inhibitor, FAK inhibitor
Related drugs:
11d
New P1 trial
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APG-2449
11ms
APG-2449 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
P1, N=150, Recruiting, Ascentage Pharma Group Inc.
Trial completion date • Trial primary completion date • Metastases
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ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ALK positive • ROS1 fusion • ROS1 positive • ALK-ROS1 fusion
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APG-2449
over1year
ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant lung cancer cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. (PubMed, Neoplasia)
Three tested ALK-TKIs including APG-2449, brigatinib and alectinib effectively and preferentially inhibited Akt/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation of the biological significance of DR4 downregulation in ALK-targeted cancer therapy.
Journal
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ALK (Anaplastic lymphoma kinase) • TNFRSF10A (TNF Receptor Superfamily Member 10a) • JUN (Jun proto-oncogene)
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ALK rearrangement • ALK mutation
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Alecensa (alectinib) • Alunbrig (brigatinib) • APG-2449
over1year
MDM2 inhibitor alrizomadlin (APG-115) promotes antitumor activity of mitogen-activated protein kinase (MAPK) inhibitors in uveal melanoma (AACR 2023)
When combined with inhibitors against mitogen-activated protein kinase kinase (MEK) [trametinib and selumetinib], mammalian target of rapamycin (mTOR) [rapamycin], focal adhesion kinase (FAK) [defactinib and Ascentage’s APG-2449, which targets FAK/ALK/ROS1], and MEK/rapidly accelerated fibrosarcoma [RAF] [VS-6766], alrizomadlin demonstrated enhanced antiproliferative activity. Combining MEK and FAK inhibitors also markedly augmented caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage (apoptosis hallmarks) and enhanced observed antitumor effects. In conclusion, our results demonstrate the potential utility of combining alrizomadlin with MAPK pathway inhibitors to treat patients with UM.
PARP Biomarker
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ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • mTOR (Mechanistic target of rapamycin kinase) • MAPK1 (Mitogen-activated protein kinase 1) • CASP3 (Caspase 3) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
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TP53 mutation
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Mekinist (trametinib) • Koselugo (selumetinib) • avutometinib (VS-6766) • alrizomadlin (APG-115) • defactinib (VS-6063) • APG-2449
over2years
Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models. (PubMed, BMC Cancer)
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.
Preclinical • Journal
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CD44 (CD44 Molecule) • ALDH1A1 (Aldehyde Dehydrogenase 1 Family Member A1)
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EGFR mutation • ALK fusion • ALK mutation • ROS1 mutation
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Mekinist (trametinib) • Tagrisso (osimertinib) • carboplatin • paclitaxel • APG-2449
over2years
First-in-human phase I results of APG-2449, a novel FAK and third-generation ALK/ ROS1 tyrosine kinase inhibitor (TKI), in patients (pts) with second-generation TKI-resistant ALK/ROS1+ non–small cell lung cancer (NSCLC) or mesothelioma. (ASCO 2022)
Another pt with the G1202R mutation following alectinib treatment had tumor shrinkage of 27.9%. APG-2449 has a favorable safety and PK profile and was well tolerated in 84 subjects. Preliminary efficacy was observed in pts whose disease was resistant to second-generation TKIs, especially among those with brain metastases, and in TKI-naïve pts. Biomarker data indicated potential target engagement on FAK and immunomodulatory effects of APG-2449.
Clinical • P1 data
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ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IFNG (Interferon, gamma)
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ALK mutation • ALK G1202R • ALK C1156Y • ALK G1269A • ALK I1171 • ALK L1196M • ALK E1210K • ALK I1171S • ALK V1180L
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Alecensa (alectinib) • APG-2449
over2years
APG-2449 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
P1, N=150, Recruiting, Ascentage Pharma Group Inc. | N=100 --> 150 | Trial completion date: May 2023 --> Feb 2025 | Trial primary completion date: May 2022 --> Jan 2025
Enrollment change • Trial completion date • Trial primary completion date
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ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ALK positive • ROS1 fusion • ROS1 positive • ALK-ROS1 fusion
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APG-2449
over2years
FAK inhibitor APG-2449 and CDK4/6 inhibitor palbociclib synergistically suppress mesothelioma tumor growth via autophagy induction (AACR 2022)
The synergistic effects are evidently mediated by induced autophagy and enhanced cellular senescence. This preclinical study lays a foundation for future clinical development of APG-2449 combined with CDK4/6 inhibitors for mesothelioma.
IO biomarker
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ALK (Anaplastic lymphoma kinase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NF1 (Neurofibromin 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • NF2 (Neurofibromin 2) • HMGB1 (High Mobility Group Box 1)
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CDKN2A deletion • NF2 negative
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Ibrance (palbociclib) • APG-2449
4years
A multi-kinase inhibitor APG-2449 enhances the antitumor effect of Ibrutinib in esophageal squamous cell carcinoma via EGFR/FAK pathway inhibition. (PubMed, Biochem Pharmacol)
In ESCC xenotransplantation models, single therapy with either ibrutinib or APG-2449 was equivalent in delaying tumor growth, while the combination therapy suppressed tumor growth more significantly. Our data strongly suggest that the combination therapy of APG-2449 and ibrutinib can provide an effective therapeutic strategy for ESCC patients, which deserved further clinical investigation.
Journal
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HER-2 (Human epidermal growth factor receptor 2)
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HER-2 amplification
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Imbruvica (ibrutinib) • APG-2449