Iclusig (ponatinib)

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

We report the case of a 63-year-old woman with a history of CML with poor response to imatinib who progressed to myeloid BP-CML, driven by the acquisition of t(8;21)(q22;q22)/RUNX1::RUNX1T1. The patient received intensive chemotherapy and dasatinib, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT)...Ponatinib and azacitidine were started as salvage treatment, allowing for the achievement of complete remission with deep molecular response after five cycles. Advances in the knowledge of disease biology and clonal evolution are crucial for optimal treatment selection, which ultimately translates into better patient outcomes.

Then we detected 6 repurposable drug molecules (Entrectinib, Imatinib, Ponatinib, Sorafenib, Retevmo, and Pazopanib) by molecular docking with KGs-mediated receptor proteins, ADME/T analysis, and cross-validation with the independent receptors. Therefore, these findings might be useful resources for wet lab researchers and clinicians to consider an effective treatment strategy against THCA.

P2, N=67, Active, not recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Recruiting --> Active, not recruiting

Currently, ponatinib is the only approved tyrosine kinase inhibitor (TKI) that is effective for Ph-positive ALL with the T315I mutation...is a retrospective observational study, it offers prospects for the efficacy of chemotherapy combined with the novel third-generation TKI, olverembatinib, in these conditions, which may be validated in future prospective clinical trials...Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19804.

We regarded ABL1, EGFR, and LCK as on-target kinases; among the two corresponding on-target kinase inhibitors, osimertinib and ponatinib emerged as on-target drugs whose target kinases were significantly activated. The remaining 26 kinases and seven kinase inhibitors were excluded as off-targets. Our pharmacoproteomic approach enabled the identification of on-target kinase inhibitors that are useful for drug repositioning.

Additionally, the drug combination significantly diminished the expression of YAP1, the cell proliferation marker and an antioxidant regulator, and increased oxidative stress-responsive markers in the xenograft model. In conclusion, targeting oxidative stress resistance with combined buparlisib and ponatinib suppressed tumor growth and migration by repressing IRS1-related pathways and ultimately inducing oxidative damage, suggesting the potential for targeted therapy and clinical trials in CCA patients over the use of a single drug.

With the Genomics of Drug Sensitivity in Cancer database, we found that the gastric adenocarcinoma patients with high risk-score may be sensitive to Pazopanib, XMD8.85, Midostaurin, HG.6.64.1, Elesclomol, Linifanib, AP.24534, Roscovitine, Cytarabine, and Axitinib. The gene signature consisting of the NDUFA4L2, ANKRD45, and AQP3 genes is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics, the depressive risk, and the therapy candidates for gastric adenocarcinoma patients.

In this longitudinal study, we analyzed the capacity of ponatinib to induce an antiviral response against HIV-1 infection in peripheral blood mononuclear cells (PBMCs) obtained from people with CML previously treated with imatinib for a median of 10 years who changed to ponatinib for 12 months to boost the anticancer response before discontinuing any TKI as part of the clinical trial NCT04043676. This cytotoxic immunity was mostly based on higher levels of Natural Killer and Tγδ cells seemingly boosted by ponatinib. In conclusion, transient treatment with immunomodulators like ponatinib along with ART could be explored to boost the antiviral activity of cytotoxic cells and contribute to the elimination of HIV-1 reservoir.

As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo Our study included standard-of-care agents (e.g., imatinib and nilotinib), and second-generation ABL inhibitors including ponatinib and bosutinib designed to mitigate drug resistance. Significance Statement This study examines the effects of clinically relevant small molecule BCR-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (e.g., imatinib, ponatinib) with well-characterized effects on platelet function, to discern potential anti-platelet and other effects of BCR-ABL TKIs and inform clinical safety.

No abstract available

The safety profile was generally manageable. This study suggests that olverembatinib-based therapy is another promising option for BCR::ABL1-positive ALL in addition to ponatinib, especially for patients with MRD-positive disease and a single T315I mutation.

Our findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.

The tyrosine kinase inhibitors (TKIs) represented by Imatinib are the key clinical therapy to the CML. While the mutations on the target lead to the serious drug resistance problems, especially the T315I mutation remains an unresolved challenge, and the cardiotoxicity has limited the clinical application of the third generation TKI Ponatinib despite its favorable efficacy against the T315I mutation...Herein, we present a series of novel BCR-ABL/T315I tyrosine kinase inhibitors obtained by virtual screening using ZINC21710815, a BCR-ABL/T315I inhibitor reported earlier by our team, as a lead compound, and structural optimization of lead compounds against the T315I mutation, as well as screening of two novel compounds by activity evaluation and mechanistic studies, W4 and W8. W4 and W8 have better cell death-inducing effects and special selectivity against BaF3/T315I, which are worthy of further in-depth study to obtain more desirable anti-CML drugs as lead compounds.

P1/2, N=15, Recruiting, University of Chicago | Active, not recruiting --> Recruiting

For 16 years, the patient maintained chronic phase (CP) under treatment with first- and second-generation tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib, and bosutinib, none of which resulted in ABL1 mutations. This case illustrates the critical role of third-generation TKIs like ponatinib in managing advanced CML phases, especially when previous therapies fail. It also emphasizes the necessity of vigilant long-term monitoring during the chronic phase to detect and address any signs of disease progression promptly.

The combination of decitabine, venetoclax, and ponatinib is safe and shows promising activity in patients with advanced phase chronic myeloid leukaemia, including those with multiple previous therapies or high-risk disease features. Further studies evaluating chemotherapy and venetoclax-based combination strategies using newer-generation BCR::ABL1 tyrosine kinase inhibitors are warranted.

P2, N=26, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1/2, N=15, Active, not recruiting, University of Chicago | Not yet recruiting --> Active, not recruiting | N=33 --> 15 | Initiation date: Apr 2025 --> Sep 2024

We showed that naringenin reduces viability of a panel of CML cell lines regardless of varying cellular origin and genetic mutations, and acts synergistically with dasatinib and ponatinib. Importantly, this combination was well-tolerated, with no adverse effects on body weight observed. These findings suggest that naringenin, by inducing oxidative lipid damage, enhances the anti-leukemic effects of Bcr-Abl TKIs, offering a promising therapeutic strategy for CML.

These derivatives were compared to the known tyrosine-kinase inhibitors in treating Chronic Myeloid Leukemia, i.e., imatinib and ponatinib. The addition of a methylpiperazine ring seems to be well distributed in the structure of afatinib when targeting the BCR-ABL enzyme, providing an important hydrogen bond interaction with the Asp381 residue of the DFG-switch of BCR-ABL active site residue and the AFA(IV) new chemical entities. Finally, in silico toxicity predictions show a favorable index, with some molecules presenting the loss of the irritant properties associated with afatinib in theoretical predictions.

The current availability of six different TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib) in clinical practice makes it important to know their efficacy and toxicity profile for treatment optimization. In summary, the latest research highlights the versatility of bosutinib in CML treatment and underscores its pivotal role in optimizing patient management in challenging cases. Continuing research and investigation will further establish bosutinib's place in the evolving landscape of CML therapy, offering an alternative for CML patients across different treatment stages.

P2, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

BCR-ABL1 compound mutations can lead to resistance to ABL1 inhibitors in chronic myeloid leukemia (CML), which could be targeted by combining the ATP-site inhibitor ponatinib and the allosteric inhibitor asciminib. Here, we report the clinical validation of this approach in a CML patient, providing a basis for combination therapy to overcome such resistance.

Significant progress has been made in recent years in the treatment of adults with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL).1 Combining BCR::ABL1 tyrosine kinase inhibitors (TKIs) with intensive chemotherapy regimens like hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD) and others has greatly improved patient outcomes.2 As a result, allogeneic hematopoietic stem cell transplantation (HSCT) has become an additional valuable option...Specifically, the 5-year PFS rates were 81% with hyper-CVAD plus ponatinib, 54% with hyper-CVAD plus dasatinib, and 64% with hyper-CVAD plus imatinib...In contrast to the D-ALBA trial, only two patients underwent HSCT.26 Whether the combination of blinatumomab and ponatinib can overcome the poor prognosis of IKZF1plus and the negative impact of an elevated white blood cell count (higher than 70×109/L, as shown in a multivariate analysis to correlate with a higher risk of relapse) remains to be determined.Asciminib is a first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor that was evaluated in combination with dasatinib and prednisone in a phase 1 trial of 25 patients with Ph-positive ALL, with a median age of 65 years (range, 33 to 85 years).27 Fourteen patients were enrolled in the dose-escalation cohort and 11 in the dose-expansion cohort...Eighteen patients with newly diagnosed Ph-positive ALL received dasatinib/vincristine/prednisone followed by sequential infusions of CD19 and CD22 CAR T cells...The chemotherapy-free regimens involving TKIs alongside blinatumomab have demonstrated outstanding outcomes in the frontline setting, particularly with the utilization of ponatinib. The combination of ponatinib and blinatumomab exhibits high efficacy, with CMR rates of 83% by PCR and 98% by ClonoSEQ and a 3-year OS rate of 91%, with only two patients undergoing HSCT.

P2, N=283, Active, not recruiting, Takeda | Trial completion date: Jun 2024 --> Dec 2024

P2, N=4, Terminated, Institute of Hematology and Blood Transfusion, Czech Republic | N=32 --> 4 | Suspended --> Terminated; slower recruitment rate;

P1/2, N=60, Recruiting, Incyte Biosciences International Sàrl | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Dec 2024 --> Jan 2026

P1/2, N=11, Completed, Takeda | Active, not recruiting --> Completed | N=68 --> 11 | Trial completion date: Jan 2027 --> Jul 2024 | Trial primary completion date: Dec 2024 --> Dec 2023

EMPA attenuates PON-induced cardiotoxicity by reducing senescence, enhancing the SRE-SRF binding and restoring the connexin 43-autophagy pathway. This effect may pave the way to use of SGLT2 inhibitors in attenuating tyrosine-kinase inhibitor cardiotoxicity.

Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first-line treatment of newly diagnosed CML in the chronic phase (CML-CP)...Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least two TKIs and for all patients in advanced-phase disease. Older patients who have a cytogenetic relapse post-failure on all TKIs can maintain long-term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, and others).

P2, N=25, Recruiting, University of Chicago | Trial completion date: May 2026 --> Mar 2025 | Trial primary completion date: Jun 2024 --> Mar 2025

P2, N=20, Not yet recruiting, Novartis Pharmaceuticals

Other generation ABL tyrosine kinase inhibitors such as dasatinib, nilotinib, bosutinib and ponatinib help to overcome imatinib resistance [3]. ATP binding P-Loop (42.42 %), Direct binding site (36.36 %), C-Loop (10.60 %), A-Loop (6.06 %), SH2 contact (3.03 %), SH3 contact (1.51 %). Total 20.06 % patients (66/329) show mutation in at least one of the structural motifs of BCR-ABL kinase domain, which further confer the resistance to a particular generation of TKI.

Asciminib broadens therapeutic choices for patient's refractory or intolerant to two prior lines of treatment in a cost-effective manner. The costs of drugs significantly impact the overall cost of the disease, emphasizing the importance of the selected discount rates for each drug. Given the relatively low incidence of CML, the introduction of asciminib has a limited budgetary impact, warranting individualized decisions based on patient`s clinical characteristics.

The present study investigates the effects of three BCR::ABL1 inhibitors, ponatinib, nilotinib and imatinib, on angiogenesis and signalling in human endothelial cells in response to vascular endothelial growth factor (VEGF). These results support the notion that the vascular endothelium is a site of action of BCR::ABL1 inhibitors from which side effects may arise, and that the different vascular toxicity profiles of BCR::ABL1 inhibitors may be due to their different actions at the molecular level. In addition, the as yet unknown pro-angiogenic effect of nilotinib should be considered in the treatment of patients with comorbidities associated with pathological angiogenesis, such as ocular disease, arthritis or obesity.

CPNE1 could be a predictive biomarker and a potential target for biological therapy in STAD.

Additionally, both tofacitinib and ponatinib cause impairment in AhR-regulated CYP1A1 enzyme activity induced by potent AhR agonists. This study unveils ponatinib and tofacitinib as potential modulators of AhR, providing valuable insights into their therapeutic roles in AhR-associated diseases and enhancing our understanding of the intricate relationship between kinase inhibitors and AhR.

P1/2, N=11, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed

Inhibiting each of these metabolic pathways overcame ponatinib adaptation of GSCs, but interrogation of patient data revealed sphingolipid degradation as the most relevant pathway in GBM. Our data highlight that targeting lipid metabolism, and particularly sphingolipid degradation in combinatorial therapies, could improve the outcome of TKI therapies using ponatinib in GBM.

The disengaged molecular brake and engaged hydrophobic spine were believed to be the driving factors for weak protein-ligand interaction. Taken together, the inhibitory and structural characteristics exhibited by ponatinib may aid in thwarting resistance based on Val-to-Met gatekeeper mutations at an earlier stage of treatment and advance the design and development of other inhibitors targeted at FGFRs harboring gatekeeper mutations.

P=N/A, N=30, Not yet recruiting, Peking University People's Hospital | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2026