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1m
In-depth theoretical modeling to explore the mechanism of TPX-0131 overcoming lorlatinib resistance to ALKL1196M/G1202R mutation. (PubMed, Comput Biol Med)
The tight binding of TPX-0131 to residues Arg1202, Met1199 and Arg1120 contribute significantly to overcoming lorlatinib resistance in ALKL1196M/G1202R mutant. These research results are expected to offer insights into the mechanism of TPX-0131 in treating ALKG1202R/L1196M-induced NSCLC resistance and optimizing of ALK inhibitors.
Journal
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ALK (Anaplastic lymphoma kinase)
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ALK mutation • ALK G1202R • ALK L1196M
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Lorbrena (lorlatinib) • TPX-0131
2ms
Brain Exposure to the Macrocyclic ALK Inhibitor Zotizalkib is Restricted by ABCB1, and Its Plasma Disposition is Affected by Mouse Carboxylesterase 1c. (PubMed, Mol Pharm)
Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC)...ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities...Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors.
Preclinical • Journal
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ALK (Anaplastic lymphoma kinase) • ABCB1 (ATP Binding Cassette Subfamily B Member 1) • ABCG2 (ATP Binding Cassette Subfamily G Member 2) • CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4) • SLCO1C1 (Solute Carrier Organic Anion Transporter Family Member 1C1)
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ALK mutation
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TPX-0131 • elacridar (GF120918)
4ms
An ultra-fast green ultra-high-performance liquid chromatography-tandem mass spectrometry method for estimating the in vitro metabolic stability of zotizalkib in human liver microsomes. (PubMed, J Sep Sci)
Zotizalkib (ZTK, TPX-0131) is a fourth-generation highly effective inhibitor of wild-type anaplastic lymphoma kinase (ALK) and ALK-resistant mutations that can penetrate the central nervous system...ZTK and encorafenib were separated using an Agilent C8 column (Eclipse Plus) and an isocratic mobile phase...The in vitro half-life (t1/2) and intrinsic clearance (Clint) of ZTK were determined to be 15.79 min and 51.35 mL/min/kg, respectively that suggests the ZTK exhibits characteristics similar to those of a medication with a high extraction ratio. These approaches are crucial for the progress of novel pharmaceutical development, especially in improving metabolic stability.
Preclinical • Journal
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ALK (Anaplastic lymphoma kinase)
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Braftovi (encorafenib) • TPX-0131
10ms
A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations. (PubMed, Front Mol Biosci)
This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.
Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK rearrangement • ALK mutation • ALK F1174C • ALK F1174V
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Lorbrena (lorlatinib) • Augtyro (repotrectinib) • TPX-0131
over1year
A Study of TPX-0131, a Novel Oral ALK Tyrosine Kinase Inhibitor, in Patients With ALK+ Advanced or Metastatic NSCLC (clinicaltrials.gov)
P1/2, N=11, Terminated, Turning Point Therapeutics, Inc. | Trial completion date: Aug 2026 --> Apr 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Apr 2025 --> Apr 2023; Adverse change in the risk/benefit.
Trial completion date • Trial termination • Trial primary completion date • Metastases
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ALK (Anaplastic lymphoma kinase)
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TPX-0131
over1year
Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review. (PubMed, Transl Lung Cancer Res)
Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4 generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. Strategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control.
Review • Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK rearrangement
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TPX-0131 • NVL-655
2years
A Study of TPX-0131, a Novel Oral ALK Tyrosine Kinase Inhibitor, in Patients With ALK+ Advanced or Metastatic NSCLC (clinicaltrials.gov)
P1/2, N=11, Active, not recruiting, Turning Point Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=210 --> 11
Enrollment closed • Enrollment change • Metastases
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ALK (Anaplastic lymphoma kinase)
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TPX-0131
2years
Prediction of Resistance Mutations Against Upcoming Anaplastic Lymphoma Kinase Inhibitors. (PubMed, Target Oncol)
We developed a PCR-based system for predicting drug resistance mutations. When this system was applied to repotrectinib and ensartinib, the results suggested that these drugs can be used for the second-line treatment of ALK-positive NSCLC. Predicting resistance mutations against TKIs will provide useful information to aid in the development of effective therapeutic strategies.
Journal
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ALK (Anaplastic lymphoma kinase) • FLT3 (Fms-related tyrosine kinase 3)
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ALK positive • ALK mutation
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Alecensa (alectinib) • Xospata (gilteritinib) • Ensacove (ensartinib) • Augtyro (repotrectinib) • TPX-0131
3years
A Study of TPX-0131, a Novel Oral ALK Tyrosine Kinase Inhibitor, in Patients With ALK+ Advanced or Metastatic NSCLC (clinicaltrials.gov)
P1/2, N=210, Recruiting, Turning Point Therapeutics, Inc. | Initiation date: Mar 2021 --> Aug 2021
Trial initiation date
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ALK (Anaplastic lymphoma kinase)
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TPX-0131
over3years
Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC? (PubMed, Transl Oncol)
How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities ("singe mutant active" versus "double mutant active") rather than the loosely-defined "generational" (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs.
Clinical • Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK fusion • ALK mutation
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TPX-0131 • NVL-655
over3years
TPX-0131, a Potent CNS-Penetrant, Next-Generation Inhibitor of Wild-Type ALK and ALK-Resistant Mutations. (PubMed, Mol Cancer Ther)
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, ALK inhibitors have become important treatments for a subset of patients with lung cancer...The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations)...Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were ~66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against wild-type ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.
Journal
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ALK (Anaplastic lymphoma kinase)
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ALK fusion • ALK mutation • ALK G1202R • ALK L1196M
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Xalkori (crizotinib) • Lorbrena (lorlatinib) • TPX-0131
over3years
Clinical • New P1/2 trial
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ALK (Anaplastic lymphoma kinase)
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TPX-0131