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TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations
Brion W Murray1, Dayong Zhai2, Wei Deng2
1Turning Point Therapeutics, San Diego, California. brion.murray@tptherapeutics.com.
Molecular Cancer Therapeutics
|June 23, 2021
Summary
TPX-0131 is a novel anaplastic lymphoma kinase (ALK) inhibitor demonstrating potent activity against wild-type ALK and resistance mutations. This next-generation therapy shows promise for lung cancer patients with limited treatment options.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Anaplastic lymphoma kinase (ALK) inhibitors have advanced lung cancer treatment since 2011.
- Existing ALK inhibitors face limitations due to resistance mutations, particularly solvent front (G1202R) and gatekeeper (L1196M) mutations, and compound mutations.
- Third-generation inhibitors like lorlatinib still face challenges with acquired resistance.
Purpose of the Study:
- To evaluate TPX-0131, a novel compact macrocyclic molecule, as a next-generation ALK inhibitor.
- To assess TPX-0131's potency against wild-type (WT) ALK and various ALK resistance mutations, including compound mutations.
- To determine TPX-0131's efficacy and central nervous system (CNS) penetration in preclinical models.
Main Methods:
- In vitro cellular and biochemical assays were used to determine TPX-0131's potency against WT ALK and 26 ALK mutants.
- Xenograft models dependent on ALK (G1202R) and compound mutations were utilized to assess in vivo efficacy.
- Pharmacokinetic studies in rats measured TPX-0131 brain and plasma levels after oral administration.
Main Results:
- TPX-0131 demonstrated superior potency against WT ALK and numerous ALK resistance mutations compared to approved ALK inhibitors.
- TPX-0131 potently inhibited WT ALK and 26 ALK mutants (IC50 <10 nmol/L) in biochemical assays.
- TPX-0131, unlike lorlatinib, achieved complete tumor regression in xenograft models with G1202R and compound ALK mutations, and showed significant CNS penetration (brain levels ~66% of plasma).
Conclusions:
- TPX-0131 is a potent, CNS-penetrant, next-generation ALK inhibitor effective against a broad spectrum of ALK resistance mutations.
- TPX-0131 shows particular promise for treating lung cancer patients with G1202R solvent front mutations and compound mutations, where current therapies are limited.
- Preclinical data support TPX-0131's potential as a valuable therapeutic option for ALK-positive lung cancer with acquired resistance.
