Database Query Results : Adagrasib, ,

Adag, Adagrasib: Click to Expand ⟱
Features:
Adagrasib is a small molecule inhibitor of the KRAS G12C mutation, which is a common driver mutation in various types of cancer, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic cancer.

Adagrasib — an orally bioavailable, covalent, allele-selective small-molecule inhibitor of KRAS G12C (also known as MRTX849; brand name KRAZATI) that irreversibly binds the mutant cysteine in the KRAS switch-II pocket to suppress downstream RAS–MAPK signaling in KRAS G12C–mutant tumors. It is a targeted anticancer drug (small-molecule covalent oncoprotein inhibitor) developed for KRAS G12C–driven malignancies, with FDA accelerated approval as monotherapy in previously treated KRAS G12C–mutated advanced NSCLC, and (more recently) an FDA accelerated approval for KRAS G12C–mutated metastatic/locally advanced colorectal cancer in combination with cetuximab (EGFR blockade) after standard chemotherapy.

Primary mechanisms (ranked):

  1. Covalent inhibition of KRAS G12C (switch-II pocket binding) → blockade of KRAS signaling output.
  2. Downstream suppression of RAF–MEK–ERK (MAPK) and (context-dependent) PI3K–AKT signaling driven by KRAS G12C.
  3. Adaptive/feedback signaling rewiring (context-dependent RTK/EGFR pathway reactivation); clinical leverage in CRC via concurrent EGFR inhibition (cetuximab) to blunt feedback escape.

Bioavailability / PK relevance: Oral dosing (commonly 600 mg twice daily in labeled settings). Clinically relevant systemic exposure is achievable, but GI intolerance and hepatotoxicity frequently drive dose interruptions/reductions. Notable PK/interaction constraints include CYP3A-mediated metabolism and clinically important drug–drug interaction potential (e.g., strong CYP3A modulators) plus exposure effects with acid-reducing agents; QT prolongation risk is an additional exposure-linked constraint.

In-vitro vs systemic exposure relevance: Primary pharmacology is concentration- and target-occupancy–driven with on-target KRAS G12C covalent engagement; many pathway-level in-vitro effects occur at exposures that may not be uniformly achievable across tumors because of heterogeneity in drug delivery, efflux/uptake, and adaptive signaling. No external trigger is required.

Clinical evidence status: Established clinical activity in KRAS G12C–mutated NSCLC after prior therapy (single-arm phase 2 registrational cohort supporting accelerated approval) with documented objective responses and intracranial activity in a subset; additional confirmatory/comparative and combination trials are ongoing. In KRAS G12C–mutated colorectal cancer, combination with cetuximab has clinically meaningful response rates supporting accelerated approval in later-line disease.


Mechanism of Action:
Adagrasib works by selectively inhibiting the activity of the KRAS G12C protein, which is a key player in the RAS/MAPK signaling pathway. By blocking the activity of KRAS G12C, adagrasib prevents the growth and proliferation of cancer cells, leading to tumor shrinkage and improved survival.

Adagrasib is a promising treatment for patients with NSCLC and CRC who have the KRAS G12C mutation. Its ability to selectively inhibit KRAS G12C activity makes it a valuable option for patients who have limited treatment options. However, resistance to adagrasib can occur, and combination therapy may be necessary to overcome this resistance.

Adagrasib is a novel KRAS G12C inhibitor that targets the mutant KRAS protein by covalently binding to its switch II pocket, thereby locking it in an inactive form. This inhibition blocks critical downstream signaling pathways, such as RAF/MEK/ERK and potentially PI3K/AKT/mTOR, which are essential for tumor growth and survival. Clinically, adagrasib is being developed and used primarily to treat NSCLC and other solid tumors with the KRAS G12C mutation, providing a targeted therapy option in a subset of cancers that historically have few effective targeted treatments.

Adagrasib — mechanistic axis ranking for oncology relevance

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 KRAS G12C oncoprotein activity ↓ KRAS G12C signaling output (allele-selective) ↔ (limited direct effect; depends on presence of KRAS G12C) P Direct on-target covalent inhibition Core MOA: irreversible engagement of mutant KRAS cysteine; efficacy depends on KRAS G12C dependency and effective intratumoral exposure.
2 RAF–MEK–ERK (MAPK) signaling ↓ pERK / proliferative signaling; ↓ growth/survival programs ↔ to ↓ (context-dependent off-tumor pathway effects) P/R Pathway suppression downstream of KRAS Primary therapeutic leverage in KRAS G12C–addicted tumors; depth/durability limited by feedback and bypass signaling.
3 RTK–EGFR feedback bypass ↑ RTK/EGFR signaling (adaptive; model-dependent) unless co-inhibited ↔ R/G Adaptive resistance circuitry Clinically exploited in CRC by combining adagrasib with cetuximab to blunt EGFR-driven MAPK reactivation.
4 PI3K–AKT–mTOR ↓ (context-dependent; partial pathway dampening) ↔ R Secondary survival pathway modulation Magnitude varies by lineage, co-mutations (e.g., STK11/KEAP1), and RTK feedback intensity.
5 Cell-cycle progression and apoptosis balance ↓ proliferation; ↑ apoptosis (context-dependent) ↔ G Phenotype-level tumor control Downstream consequence of KRAS pathway suppression; tumor microenvironment and co-genetics shape whether cytostatic vs cytotoxic responses dominate.
6 Immune context and combination leverage (context-dependent) ↑ immune-mediated control with rational combinations ↔ G Combination-dependent disease control Clinical development includes combinations with immune checkpoint blockade and chemotherapy in selected settings; benefit is regimen- and population-dependent.
7 Clinical Translation Constraint GI toxicity, hepatotoxicity, ILD/pneumonitis (rare but serious), QT prolongation; CYP3A/DDI constraints; variable CNS and intratumoral exposure Same safety/PK constraints — Limits dose intensity and durability Accelerated approvals rely on ORR/DOR; confirmatory evidence and optimal sequencing vs other KRAS G12C inhibitors/combinations remain active questions.


Scientific Papers found: Click to Expand⟱
1002- SSE,  Osi,  Adag,    Selenite as a dual apoptotic and ferroptotic agent synergizes with EGFR and KRAS inhibitors with epigenetic interference
- in-vitro, Lung, H1975 - in-vitro, Lung, H385
Apoptosis↑, Ferroptosis↑, DNMT1↓, TET1↑, TumCCA↑, cl‑PARP↑, cl‑Casp3↑, Cyt‑c↑, BIM↑, NOXA↑, Apoptosis↑, ROS↑, ER Stress↑, UPR↑,

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↑, 1,   ROS↑, 1,  

Cell Death ⓘ

Apoptosis↑, 2,   BIM↑, 1,   cl‑Casp3↑, 1,   Cyt‑c↑, 1,   Ferroptosis↑, 1,   NOXA↑, 1,  

Protein Folding & ER Stress ⓘ

ER Stress↑, 1,   UPR↑, 1,  

DNA Damage & Repair ⓘ

DNMT1↓, 1,   cl‑PARP↑, 1,  

Cell Cycle & Senescence ⓘ

TumCCA↑, 1,  

Migration ⓘ

TET1↑, 1,  
Total Targets: 14

Pathway results for Effect on Normal Cells:


Total Targets: 0

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#:254  Target#:%  State#:%  Dir#:%
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