TP-3654
Source TP-3654 at Peptiology
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Summary
TP-3654 is an experimental small‑molecule inhibitor of the PIM family of serine‑threonine kinases, primarily PIM1. Pre‑clinical studies have examined its ability to reduce fibrosis, overcome drug resistance, and enhance the activity of other anticancer agents in models of skeletal‑muscle atrophy, myelofibrosis, acute myeloid leukemia, and renal cell carcinoma. A separate peptide bearing the same identifier has been radiolabelled with Tc‑99m for imaging VIP‑receptor‑positive tumours.
Mechanism of Action
TP-3654 binds to the ATP‑binding pocket of PIM kinases, blocking their catalytic activity. Inhibition of PIM1 diminishes downstream AKT phosphorylation, reduces TGF‑β/Smad signalling, and suppresses mTORC1 and MYC pathways. In cancer cells it interferes with the drug‑efflux function of ABCG2, enhancing intracellular concentrations of chemotherapeutics, and in combination with FLT3 inhibition activates GSK‑3β, promoting proteasomal degradation of c‑Myc and Mcl‑1. The radiolabelled peptide version targets VIP receptors for tumor imaging.
What the Research Shows
Animal and cell‑culture studies show that TP-3654 reduces fibroblast proliferation, induces apoptosis, and attenuates TGF‑β‑driven extracellular‑matrix deposition, thereby limiting skeletal‑muscle fibrosis after spinal‑cord injury. In murine myelofibrosis models, oral or systemic TP-3654 lowered leukocytosis, splenomegaly, and bone‑marrow fibrosis, especially when combined with the JAK inhibitor ruxolitinib. In vitro, TP-3654 restores sensitivity of ABCG2‑overexpressing multidrug‑resistant cancer cells to topotecan, SN‑38 and mitoxantrone, and synergises with the FLT3 inhibitor gilteritinib in FLT3‑ITD AML by activating GSK‑3β and degrading c‑Myc and Mcl‑1. In renal‑cell carcinoma, TP-3654 induces REDD1, sensitising cells to autophagy inhibition by chloroquine. A Tc‑99m‑labelled VIP analogue (TP 3654) demonstrated rapid tumour localisation and renal clearance in human imaging studies without acute adverse effects.
Reported Benefits
Pre‑clinical evidence suggests TP-3654 can (1) limit fibrotic remodeling in injured muscle, (2) mitigate bone‑marrow fibrosis and splenomegaly in myelofibrosis models, (3) overcome ABCG2‑mediated drug resistance in cancer cells, (4) enhance FLT3‑inhibitor efficacy in FLT3‑ITD AML via GSK‑3β activation, and (5) increase the therapeutic impact of autophagy inhibition in renal‑cell carcinoma through REDD1 up‑regulation. The radiolabelled peptide version appears capable of detecting VIP‑receptor‑positive tumours in humans.
Limitations of the Evidence
All efficacy data derive from in‑vitro assays or animal models; no human therapeutic trials of the kinase inhibitor have reported outcomes. The precise pharmacokinetic profile, optimal dosing, and long‑term safety in patients remain undefined. The imaging peptide is a distinct molecule, and its diagnostic utility has only been demonstrated in small volunteer cohorts. Potential off‑target effects of PIM inhibition have not been fully characterised.
Safety Considerations
The imaging study reported no acute adverse reactions after intravenous injection of Tc‑99m‑TP 3654 in volunteers. Pre‑clinical toxicity assessments for the kinase inhibitor were not detailed in the cited abstracts, and no human safety data are available. As a kinase inhibitor, off‑target inhibition of related kinases could theoretically affect hematopoiesis or metabolism, warranting cautious monitoring in future trials.
How It Is Administered
The Tc‑99m‑labelled TP 3654 peptide has been administered intravenously as a diagnostic injection. In pre‑clinical studies, TP-3654 the kinase inhibitor has been delivered systemically (e.g., oral or intraperitoneal dosing) to rodents, but specific formulation and route are not described in the published abstracts.
Routes of Administration
No administration routes recorded yet.
Goals & Uses
No goal associations recorded yet.
Contraindications
No contraindications recorded yet.
Adverse Effects
No adverse effects recorded yet.
Drug Interactions
No drug interactions recorded yet.
Population Constraints
No population constraints recorded yet.
Regulatory Status
No regulatory status recorded yet.
Evidence & Sources
- Journal ArticleLowYu X, et al.2025-01-01T00:00:00.000000Z
- Journal ArticleLowWu CP, et al.2021-01-01T00:00:00.000000Z
- Journal ArticleLowLee JK, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleLowDutta A, et al.2022-01-01T00:00:00.000000Z
- Journal ArticleLowCarew JS, et al.2025-01-01T00:00:00.000000Z
- Journal ArticleLowThakur ML, et al.2000-01-01T00:00:00.000000Z
Frequently Asked Questions
What type of compound is TP-3654?
TP-3654 is an experimental small‑molecule inhibitor of PIM kinases, especially PIM1. A separate peptide bearing the same name has been radiolabelled with technetium‑99m for tumor imaging.
Has TP-3654 been approved for any medical use?
No. All reported data are pre‑clinical or early‑phase clinical investigations. The kinase inhibitor is being studied in clinical trials for solid tumours and myelofibrosis, but it has not received regulatory approval.
How does TP-3654 help overcome drug resistance in cancer?
In cell models, TP-3654 blocks the drug‑efflux activity of the ABCG2 transporter, allowing higher intracellular levels of chemotherapy agents such as topotecan, SN‑38 and mitoxantrone, thereby restoring their cytotoxicity.
What are the known safety findings for TP-3654?
The Tc‑99m‑labelled imaging peptide showed no acute adverse events in volunteers. Safety data for the kinase inhibitor are limited to animal studies, which have not reported specific toxicities, so human safety remains uncertain.
Can TP-3654 be used together with other cancer drugs?
Pre‑clinical studies indicate synergistic effects when TP-3654 is combined with the FLT3 inhibitor gilteritinib in AML, with ruxolitinib in myelofibrosis, and with chloroquine in renal‑cell carcinoma, suggesting potential combination strategies.
What is TP-3654?
TP-3654 is an experimental small‑molecule inhibitor of the PIM family of serine‑threonine kinases, primarily PIM1. Pre‑clinical studies have examined its ability to reduce fibrosis, overcome drug resistance, and enhance the activity of other anticancer agents in models of skeletal‑muscle atrophy, myelofibrosis, acute myeloid leukemia, and renal cell carcinoma. A separate peptide bearing the same identifier has been radiolabelled with Tc‑99m for imaging VIP‑receptor‑positive tumours.