Iclusig (ponatinib)

Clinically approved multikinase inhibitors-including ponatinib, gefitinib, and regorafenib-exhibit off-target RIPK2 inhibition, while selective compounds such as WEHI-345, GSK2983559, CSLP37, UH15-15, and thienopyrimidine derivatives represent key advances in selective blockade. Despite encouraging preclinical data, no RIPK2-specific inhibitor has yet achieved clinical approval due to safety and selectivity challenges. Continued structure-guided optimization, exploration of allosteric and degradation-based mechanisms, and integration into precision-medicine frameworks may ultimately enable safe and effective RIPK2-targeted therapies for inflammatory and autoimmune disorders, while the potential application in oncology remains under preclinical investigation.

Introduction of tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 fusion protein has revolutionized frontline therapy, with successive generations of TKIs-from imatinib to dasatinib and most recently ponatinib-achieving progressively deeper and more durable molecular responses. Concurrently, the integration of immunotherapy, particularly blinatumomab, has enabled chemotherapy-sparing approaches further improving tolerability and efficacy...Treatment-free remission strategies following prolonged TKI maintenance in non-transplant patients, and the integration of chimeric antigen receptor (CAR) T-cell therapy as bridge, consolidation, or salvage, represent emerging frontiers. This review critically examines the contemporary role of allogeneic HCT in Ph+ ALL and provides a framework for transplant decision-making in the contemporary era of targeted and cellular immunotherapy.

The combination of ARV-110 and ponatinib exerted a significant inhibitory and synergistic effect on CRPC cells. Additionally, the substantial accumulation of reactive oxygen species induced by the combination strategy was related to the joint downregulation of catalase by the two drugs through different mechanisms. In conclusion, this study described a new strategy for the treatment of CRPC and clarified the molecular mechanisms of the combination strategy, providing a new theoretical basis for the precision treatment of CRPC.

In the multivariate analysis, WBC > 70,000/L at diagnosis (p = 0.01), p210 BCR::ABL1 fusion (p < 0.001) and monosomy 7 (p = 0.007) were independently associated with failure to achieve CMR, while use of ponatinib or dasatinib (p = 0.008) and intensive chemotherapy (IC) (p = 0.009) predicted higher CMR. vs. 149.3 months, p = 0.07) with or without allogeneic hematopoietic cell transplantation (allo-HCT). These findings suggest that allo-HCT may be deferred in selected patients achieving early CMR, although prospective validation is needed.

Furthermore, ponatinib increases chimeric antigen receptor (CAR) TSCM cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing TSCM cells for improved antitumor T cell activity.

P1/2, N=100, Recruiting, Cardiff University | Not yet recruiting --> Recruiting

This case highlights the clinical significance of multilineage Ph+ ALL and its distinct biological background, thereby underscoring caution with TKI discontinuation despite deep NGS MRD-negativity, and may support continued TKI therapy in this setting.

Inhibition of PGK1 initiates autophagy in T315I-mutant chronic myeloid leukemia (CML) cells, thereby enhancing their sensitivity to first-generation Tyrosine Kinase Inhibitor (TKI) imatinib and third-generation TKI ponatinib. Notably, CPU-216 induces autophagy via VCP and Beclin 1 in CML-T315I cells, enhancing their responsiveness to TKIs. These discoveries propose a novel therapeutic strategy for T315I-mutant CML, underscoring the potential to develop targeted treatments that leverage the kinase functions of PGK1.

Essential dynamics and free-energy landscape analyses, followed by MM-PBSA and per-residue analyses, supported the thermodynamic stability and favorable binding energetics of the complexes. Collectively, these findings nominate Ponatinib and Lapatinib as promising repurposing candidates for subsequent biochemical and cellular validation as AURKB inhibitors.

P3, N=348, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=25, Suspended, University of Chicago | Recruiting --> Suspended

P2, N=84, Recruiting, National Cancer Institute (NCI) | N=64 --> 84