Dasatinib/Phyrago / TumCI Cancer Research Results

DAS, Dasatinib/Phyrago: Click to Expand ⟱
Features:
Dasatinib, (brand name Sprycel) is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia and acute lymphoblastic leukemia.

Dasatinib — Dasatinib is an orally administered, small-molecule, ATP-competitive multi-target tyrosine kinase inhibitor developed as BMS-354825 and marketed historically as Sprycel. It is formally classified as a second-generation BCR-ABL1/SRC-family kinase inhibitor and antineoplastic targeted therapy. Standard abbreviations include DAS and BMS-354825. Its highest-confidence clinical identity is treatment of Philadelphia chromosome-positive chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, while solid-tumor use remains investigational or context-dependent.

Primary mechanisms (ranked):

  1. Direct inhibition of BCR-ABL1 kinase signaling in Philadelphia chromosome-positive leukemia, suppressing leukemic proliferation and survival signaling.
  2. Inhibition of SRC-family kinases including SRC, LCK, YES, FYN, LYN, and HCK, reducing alternative kinase signaling, invasion, adhesion, migration, and some imatinib-resistance pathways.
  3. Downstream suppression of STAT5, PI3K-AKT, and MAPK signaling in BCR-ABL1/SRC-dependent leukemic progenitors.
  4. Secondary inhibition of c-KIT, PDGFRβ, and EPHA2, which may be relevant in selected tumor contexts but is not the dominant approved-use mechanism.
  5. Senolytic activity in combination with quercetin, mainly through selective vulnerability of senescent cells; this is investigational and not an oncology-label mechanism.

Bioavailability / PK relevance: Dasatinib is an oral drug with rapid absorption, high plasma protein binding, large apparent distribution volume, and short terminal half-life. Standard Sprycel/generic dasatinib exposure is pH-sensitive, so proton-pump inhibitors and H2 antagonists can reduce exposure; antacids require separation. A newer FDA-approved formulation, Phyrago, is designed to reduce this gastric-acid interaction constraint. Dasatinib is primarily metabolized by CYP3A4, so strong CYP3A4 inhibitors, inducers, grapefruit juice, and St. John’s wort are major PK constraints.

In-vitro vs systemic exposure relevance: Many leukemia-cell effects occur at low nanomolar concentrations and are clinically plausible. Some solid-tumor, migration, invasion, and high-concentration mechanistic findings may exceed or poorly model achievable tumor exposure, especially because dasatinib has high protein binding and short plasma half-life. This is concentration-driven and target-dependency-driven rather than field-based.

Clinical evidence status: Approved targeted therapy with phase III evidence for Ph+ CML and established use in Ph+ ALL. Evidence in solid tumors is mostly preclinical, phase I/II, negative, or biomarker-dependent adjunct investigation. AD/senolytic use is early human proof-of-concept with dasatinib plus quercetin and is not approved disease-modifying therapy.

Dasatinib Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 BCR-ABL1 kinase addiction ↓ BCR-ABL1 signaling; ↓ proliferation; ↑ apoptosis in Ph+ leukemia ↔ in BCR-ABL1-negative cells except off-target kinase effects P,R,G Core leukemia-selective cytostatic and cytotoxic effect Highest clinical relevance in Ph+ CML and Ph+ ALL; target presence is decisive.
2 SRC-family kinase signaling ↓ SRC, LYN, HCK, LCK, YES, FYN signaling; ↓ invasion and survival signaling ↓ immune-cell and platelet signaling possible P,R,G Blocks alternative oncogenic kinase signaling and some resistance pathways Important for imatinib-resistant signaling and solid-tumor biology, but clinical benefit outside Ph+ leukemia is less consistent.
3 STAT5 survival signaling ↓ pSTAT5 downstream of BCR-ABL1 and SRC-family kinases ↓ cytokine and T-cell signaling possible R,G Reduces transcriptional survival programs Mechanistically central in CML progenitors; contributes to apoptosis and reduced colony formation.
4 PI3K-AKT and MAPK signaling ↓ AKT and ↓ MAPK signaling in dependent leukemia progenitors ↔ or ↓ growth-factor signaling depending on cell type R,G Suppresses proliferation and anti-apoptotic signaling Downstream effect rather than primary binding target; context-dependent in non-leukemia tumors.
5 c-KIT PDGFRβ EPHA2 kinase inhibition ↓ receptor kinase signaling where target-dependent ↓ normal stromal, vascular, hematopoietic, or progenitor signaling possible P,R,G Broadens kinase inhibition spectrum Mechanistically real but not the main basis of approved use.
6 Cell adhesion migration and invasion ↓ migration; ↓ invasion; ↓ metastatic behavior markers in some solid-tumor models ↓ immune-cell trafficking and platelet function possible G Anti-invasive and cytostatic effect High preclinical relevance; weaker clinical translation in unselected solid tumors.
7 Chemo sensitization ↑ sensitivity in selected combinations and biomarker contexts ↑ toxicity risk possible due to myelosuppression and bleeding G Adjunct pathway blockade Combination use requires disease-specific evidence; not broadly generalizable.
8 Radiosensitization ↑ radiosensitivity reported in some SRC-dependent preclinical models ↑ normal-tissue radiosensitivity or marrow toxicity possible G Potential adjunct radiosensitizer Not a standard approved radiosensitizer; clinical use should be considered investigational.
9 Immune and platelet signaling ↔ indirect antitumor effects; may alter immune microenvironment ↓ T-cell receptor signaling; ↓ platelet function; ↑ bleeding risk P,R,G On-target normal-cell pharmacology Clinically important safety axis, especially bleeding, infection risk, and immune modulation.
10 ROS NRF2 mitochondria ↔ or context-dependent changes; not a core dasatinib mechanism ↔ or context-dependent stress response G Secondary stress-response modulation Do not rank as a primary pathway unless a specific model demonstrates ROS-linked cytotoxicity.
11 Clinical Translation Constraint Target-negative tumors often show limited response despite kinase inhibition Myelosuppression, pleural effusion, pulmonary hypertension, QT risk, bleeding, hepatotoxicity, pregnancy risk G Limits broad repurposing Clinical translation depends on Ph+ status, kinase dependency, formulation, acid-suppression use, CYP3A4 interactions, and tolerability.

P: 0–30 min R: 30 min–3 hr G: >3 hr



Dasatinib in Alzheimer’s disease — Dasatinib is not an approved AD therapy. Its AD relevance is mainly as part of the investigational senolytic combination dasatinib plus quercetin, where intermittent dosing is intended to reduce senescent-cell burden and senescence-associated inflammatory signaling. Current evidence is early-stage human feasibility and biomarker work, not established cognitive efficacy.

Primary mechanisms (ranked):

  1. Senolytic elimination of senescent cells in combination with quercetin, potentially reducing senescence-associated secretory phenotype signaling.
  2. Reduction of neuroinflammatory and peripheral inflammatory senescence biomarkers, if senolytic activity translates into CNS-relevant exposure.
  3. Possible effects on glial senescence and vascular/neurovascular dysfunction, still investigational.
  4. PK limitation: dasatinib CNS exposure and intermittent dosing may constrain direct brain-target engagement.

Bioavailability / PK relevance: AD protocols use intermittent oral dasatinib with quercetin rather than continuous oncology dosing. The key translational question is whether adequate CNS exposure and senescent-cell selectivity occur without unacceptable toxicity in older adults.

In-vitro vs systemic exposure relevance: Senolytic effects are concentration- and cell-state-dependent. In-vitro senescent-cell killing does not automatically imply achievable, selective CNS clearance in humans.

Clinical evidence status: Early human phase I and pilot studies only. Phase II randomized testing has been registered, but dasatinib plus quercetin remains investigational for AD and mild cognitive impairment.

Dasatinib AD Senolytic Profile

Rank Pathway / Axis Modulation TSF Primary Effect Notes / Interpretation
1 Senescent-cell survival signaling ↓ senescent-cell viability with dasatinib plus quercetin G Senolytic clearance Combination-dependent; dasatinib alone should not be treated as a validated AD senolytic regimen.
2 SASP inflammatory signaling ↓ senescence-associated inflammatory mediators (context-dependent) G Potential neuroinflammation reduction Human evidence is biomarker-oriented and preliminary.
3 Glial and vascular senescence ↓ pathological senescence burden (model-dependent) G Potential support of brain microenvironment Requires demonstration of CNS exposure and clinically meaningful target engagement.
4 Cognition and function ↔ or uncertain G No established disease-modifying effect Existing studies are too small or exploratory to establish cognitive benefit.
5 Clinical Translation Constraint ↑ safety monitoring burden; ↔ efficacy unproven G Limits AD translation Older adults may be vulnerable to cytopenias, bleeding, fluid retention, drug interactions, and infection risk.

P: 0–30 min R: 30 min–3 hr G: >3 hr
TumCI, Tumor Cell invasion: Click to Expand ⟱
Source:
Type:
Tumor cell invasion is a critical process in cancer progression and metastasis, where cancer cells spread from the primary tumor to surrounding tissues and distant organs. This process involves several key steps and mechanisms:

1.Epithelial-Mesenchymal Transition (EMT): Many tumors originate from epithelial cells, which are typically organized in layers. During EMT, these cells lose their epithelial characteristics (such as cell-cell adhesion) and gain mesenchymal traits (such as increased motility). This transition is crucial for invasion.

2.Degradation of Extracellular Matrix (ECM): Tumor cells secrete enzymes, such as matrix metalloproteinases (MMPs), that degrade the ECM, allowing cancer cells to invade surrounding tissues. This degradation facilitates the movement of cancer cells through the tissue.

3.Cell Migration: Once the ECM is degraded, cancer cells can migrate. They often use various mechanisms, including amoeboid movement and mesenchymal migration, to move through the tissue. This migration is influenced by various signaling pathways and the tumor microenvironment.

4.Angiogenesis: As tumors grow, they require a blood supply to provide nutrients and oxygen. Tumor cells can stimulate the formation of new blood vessels (angiogenesis) through the release of growth factors like vascular endothelial growth factor (VEGF). This not only supports tumor growth but also provides a route for cancer cells to enter the bloodstream.

5.Invasion into Blood Vessels (Intravasation): Cancer cells can invade nearby blood vessels, allowing them to enter the circulatory system. This step is crucial for metastasis, as it enables cancer cells to travel to distant sites in the body.

6.Survival in Circulation: Once in the bloodstream, cancer cells must survive the immune response and the shear stress of blood flow. They can form clusters with platelets or other cells to evade detection.

7.Extravasation and Colonization: After traveling through the bloodstream, cancer cells can exit the circulation (extravasation) and invade new tissues. They may then establish secondary tumors (metastases) in distant organs.

8.Tumor Microenvironment: The surrounding microenvironment plays a significant role in tumor invasion. Factors such as immune cells, fibroblasts, and signaling molecules can either promote or inhibit invasion and metastasis.
Scientific Papers found: Click to Expand⟱
6590- DAS,    Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells
- in-vitro, Pca, NA
Src↓, ABL1↓, BioAv↑, TumCG↓, Dose↓, TumCA↓, TumCMig↓, TumCI↓,
6593- DAS,    Dasatinib: a potent SRC inhibitor in clinical development for the treatment of solid tumors
TumCP↓, TumCI↓, TumMeta↓, eff↑, Src↓,

Showing Research Papers: 1 to 2 of 2

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Mitochondria & Bioenergetics(tgid=3) ⓘ

ABL1↓, 1,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

Src↓, 2,   TumCG↓, 1,  

Migration(tgid=13) ⓘ

TumCA↓, 1,   TumCI↓, 2,   TumCMig↓, 1,   TumCP↓, 1,   TumMeta↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↑, 1,   Dose↓, 1,   eff↑, 1,  
Total Targets: 11

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: TumCI, Tumor Cell invasion
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:6  Target#:324  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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