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Our Science
A class of targeted drugs known as tyrosine kinase inhibitors (TKIs) has played a transformative role in modern cancer treatment. With their ability to interrupt kinase signaling that leads to unchecked cell growth and tumor progression, more than 30 have been approved since the late 1990s.
Tumors invariably become resistant to kinase inhibitors, often within one to two years.
Most kinase inhibitor molecules share a similar oversized shape and use comparable binding mechanisms. Thus, resistance to one often means resistance to all.
Our Approach
Turning Point Therapeutics exists to give patients a better option.
We have created a new generation of therapies that are different from conventional kinase inhibitors. Our compact molecules are potentially more potent and selective medicines that also hold promise to prevent and overcome resistance.
Better Fit
Smaller, more compact molecules fit directly in the ATP binding pocket to destroy cancer cells.
Avoid Resistance
Rigid 3-D structure reduces interference and potentially bypasses mutations that are responsible for resistance to early-generation kinase inhibitors.
Less Toxicity
Smaller structure is potentially less prone to common toxicity issues found in the TKI drug class.
Addressing Resistance
Cancers evolve, or mutate, to evade the effects of a drug. When confronted with kinase inhibitors, two types of mutations most commonly emerge: solvent-front mutations and gatekeeper mutations. Both are “acquired,” meaning they emerge only after a tumor is exposed to the drug.
Most of the currently approved or investigational ROS1, ALK and TRK kinase inhibitors have an extra chemical group that extends to the solvent-front area of the kinase. As a result, these drugs are vulnerable to solvent-front mutations.
We seek to overcome resistance by design.
Our therapies are designed differently. They are structurally compact, with a low molecular weight and a rigid three-dimensional structure that binds neatly inside an area of the cancer cell known as the “ATP” pocket. ATP is a critical molecule for cell energy and growth. By binding completely inside the ATP pocket, our TKIs can bind to solvent-front mutations that evade conventional TKIs.
Publications
TPX-0131, a Potent CNS-Penetrant, Next-Generation Inhibitor of Wild-Type ALK and ALK-Resistant Mutations
Molecular Cancer Therapeutics, 2021
Phase 1/2 TRIDENT-1 Study of Repotrectinib in Patients with ROS1+ or NTRK+ Advanced Solid Tumors
IASLC 2020 World Conference on Lung Cancer
Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent-Front Mutations
Cancer Discovery, 2018
Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress
2014 Journal of Medicinal Chemistry
A new challenging and promising era of tyrosine kinase inhibitors
2014 ACS Medicinal Chemistry Letters
Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)
2011 Journal of Medicinal Chemistry
Scientific Presentations
TPX-0131, a Potent Inhibitor of Wild Type ALK and a Broad Spectrum of Both Single and Compound ALK Resistance Mutations
American Association for Cancer Research 2021.
TPX-0022, a Potent MET/SRC/CSF1R Inhibitor That Modulates the Tumor Immune Microenvironment in Preclinical Models
American Association for Cancer Research 2021
Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Broad Mutant Selectivity
American Association for Cancer Research 2021
Repotrectinib Increases Effectiveness of MEK Inhibitors in KRAS Mutant Cancer Models
American Association for Cancer Research 2021
Repotrectinib Increases KRAS G12C Inhibitor Effectiveness Via Simultaneous Inhibition of SRC, FAK, and JAK2
ENA Symposium on Molecular Targets and Cancer Therapeutics 2020
TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers
ESMO 2019
Repotrectinib, a next generation TRK inhibitor, overcomes TRK resistance mutations including solvent front, gatekeeper and compound mutations
2019 American Association for Cancer Research Annual Meeting
Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations
2019 American Association for Cancer Research Annual Meeting
TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling
2019 American Association for Cancer Research Annual Meeting
TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC inhibits tumor growth by promoting anti-tumor immune responses
2019 American Association for Cancer Research Annual Meeting
WCLC 2018: Safety and Preliminary Clinical Activity of Repotrectinib(TPX-0005), a ROS1/TRK/ALK Inhibitor, in Advanced ROS1 Fusion-Positive Non-Small Cell Lung Cancer
2018 World Conference on Lung Cancer
A Phase 1 Study of the Next-Generation ALK/ROS1/TRK Inhibitor Repotrectinib (TPX-0005) in Patients with Advanced ALK/ROS1/NTRK+ Cancers (TRIDENT-1)
2018 American Society of Clinical Oncology (ASCO) Annual Meeting
TPX-0005, a highly potent TRK inhibitor, effectively overcomes clinical-resistance TRK mutations including solvent-front mutants TRKA G595R, TRKB G639R, and TRKC G623R
2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications
TPX-0005, a supreme ROS1 inhibitor, overcomes crizotinib-resistant ROS1 mutations including solvent-front mutation G2032R and gatekeeper mutation L2026M
2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications
TPX-0005, a polypharmacology inhibitor, overcomes ALK treatment resistances from acquired mutations, bypass signaling and EMT
2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications
TPX-0005 with an EGFR tyrosine kinase inhibitor (TKI) overcomes innate resistance in EGFR mutant NSCLC
IASLC 18th World Conference on Lung Cancer, October 2017, Japan