KRAS Inhibitors — The "Undruggable Target"? A Thing of the Past

Product Manager: Harrison Michael

I. The Once "Undruggable" Death Target: Why Is KRAS So Hard to Inhibit?

KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is a key member of the RAS family. Mutations in KRAS are among the most common oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer. It is estimated that KRAS mutations occur in approximately 20%-25% of solid tumors, with G12C, G12D, and G12V being the most prevalent.

For a long time, KRAS was deemed an "undruggable" and "death" target due to several reasons:

1. Lack of Drug-Binding Pockets in KRAS Structure

KRAS is a GTPase with a compact and smooth protein surface, lacking distinct "druggable pockets," making it difficult for small molecules to bind with high affinity and inhibit its function.

2. High GTP Affinity and Low GTPase Activity

KRAS activity depends on its binding state with GTP or GDP. Mutant KRAS typically shows low intrinsic GTPase activity, making it resistant to GTP hydrolysis and leading to persistent activation. Traditional small molecules struggle to bind stably to its active conformation.

3. Central Role in Multiple Critical Downstream Pathways

KRAS regulates several cancer-related pathways such as RAF-MEK-ERK and PI3K-AKT-mTOR. Persistent KRAS activation overstimulates these cascades, driving uncontrolled proliferation and resistance to apoptosis. Due to its central "hub" role, off-target effects can be severe and must be carefully addressed in drug design.

4. Lack of Effective Biomarkers and Complex Feedback Mechanisms

Mutant KRAS protein is widely expressed in both tumor and normal tissues. The lack of specific biomarkers to identify responders hampers early clinical trial success. Moreover, KRAS signaling is regulated by complex feedback loops and compensatory pathways, which contribute to drug resistance.

Despite these challenges, recent advances in science, structural biology, and covalent inhibition strategies have shattered the "undruggable" myth, opening new avenues for precise KRAS inhibition.

II. Three Strategic Approaches to Targeting KRAS: From Mutation-Specific to Pan-RAS Inhibition

Current KRAS inhibitor development mainly follows three strategies: mutation-selective inhibitors, pan-KRAS selective inhibitors, and pan-RAS inhibitors. Below is a detailed overview of representative drugs from each category:

(A) Mutation-Selective KRAS Inhibitors

These inhibitors are designed to specifically target KRAS proteins with certain point mutations. They feature high selectivity and relatively mild side effects, and are currently the most prominent research focus.

✅ Sotorasib（AMG 510）

· Company: Amgen

· Indication: FDA-approved for KRAS G12C-mutant NSCLC

· Mechanism: Covalently and irreversibly binds to the cysteine residue (Cys12) in G12C-mutant KRAS, locking it in the inactive GDP-bound state (OFF)

· Highlights: First FDA-approved KRAS inhibitor, marking the end of the "undruggable" era.

· Limitation: Only effective against G12C, which is rare in pancreatic and colorectal cancers.

✅ Adagrasib（MRTX849）

· Company: Mirati Therapeutics (now acquired by Bristol Myers Squibb)

· Indication: KRAS G12C-mutant NSCLC and colorectal cancer

· Mechanism & Advantages:

Also a covalent G12C binder;

Longer half-life (~23 hours) and better tissue penetration than Sotorasib, beneficial for brain metastases.

✅ MRTX1133

· Company: Mirati Therapeutics

· Target: KRAS G12D

· Status: Preclinical or early clinical stage

· Highlights:

Potent non-covalent inhibitor;

KRAS G12D is the most common mutation in pancreatic and colorectal cancers (>40% of KRAS mutations);

Broader potential patient population than G12C.

(B) Pan-KRAS Selective Inhibitors: Beyond Single Mutation Targeting

Compared to mutation-selective inhibitors, pan-KRAS inhibitors aim to cover multiple KRAS mutations and even wild-type KRAS. These drugs could expand patient applicability and partially overcome acquired resistance.

✅ BI-2865

· Company: Boehringer Ingelheim

· Mechanism: Inhibits multiple KRAS mutants including G12D, G12V, G12C, and G13D, as well as wild-type KRAS; spares HRAS/NRAS for specificity.

· Key Advantages:

o Covers ~95% of KRAS mutations

o Ineffective against G12R — a key exception

o Well tolerated in mice, no overt toxicity

· Clinical Significance: Establishes proof of concept for pan-KRAS inhibition and sets the stage for broader RAS-targeted therapies.

✅ JDQ443

· Company: Novartis

· Target: KRAS G12C

· Features: Although G12C-selective, structural design suggests potential for broader KRAS inhibition.

✅ KRAZATI (Adagrasib) in Combination Therapies

· Combination strategies are being explored with SHR6390 (CDK4/6 inhibitor), TNO155 (SHP2 inhibitor), etc., to achieve "functional pan-KRAS inhibition".

(C) Pan-RAS Inhibitors: Broad Spectrum Inhibition Across the RAS Family

The RAS family includes KRAS, NRAS, and HRAS. Pan-RAS inhibitors aim to simultaneously block all oncogenic RAS proteins.

✅ RMC-6236

· Company: Revolution Medicines

· Mechanism: Blocks RAS membrane localization and signaling, indirectly inhibiting active KRAS, NRAS, HRAS

· Clinical Status: Phase I trial

· Advantages:

o Targets all RAS mutation subtypes.

o Overcomes compensatory activation of NRAS or HRAS following KRAS inhibition.

· Challenges:

o Broad inhibition may cause toxicity.

o Needs further clinical validation for therapeutic index.

✅ RMC-9805 / RMC-8839

· Target: KRAS G12D / KRAS G13C

· Mechanism: Small molecules developed by Revolution Medicines using a "molecular glue" strategy, balancing pan-RAS activity with selectivity.

III. ON/OFF States and Binding Strategies: Core Drivers of KRAS Inhibitor Efficacy

KRAS alternates between an active (ON) GTP-bound state and an inactive (OFF) GDP-bound state. Most G12C mutants retain partial GTPase function, allowing transient OFF states.

Sotorasib and Adagrasib require KRAS(G12C) to switch to the GDP-bound OFF state for binding.

Mutations like G12D and G12V often "lock" KRAS in the ON state, making covalent inhibition ineffective — explaining their resistance to current inhibitors.

Emerging strategies:

Develop inhibitors that bind the GTP-bound ON state directly, or manipulate KRAS intracellular cycling to favor OFF conformations.

IV. Resistance Mechanisms to KRAS Inhibitors and Counterstrategies

Despite clinical advances, resistance remains a major challenge. Known mechanisms include:

1. Secondary Mutations:

· e.g., Emergence of G13D or G12V after Sotorasib treatment.

· Render original inhibitors ineffective.

2. Upstream/Downstream Reactivation:

· EGFR, SHP2, PI3K-AKT pathways can bypass KRAS inhibition.

3. Cellular Plasticity and Phenotypic Transformation:

· EMT, cancer stemness can reduce apoptotic response.

4. Impact of Co-mutations:

· Co-occurring mutations in TP53, STK11, KEAP1 influence drug sensitivity and immune microenvironment.

Countermeasures:

· Combination therapies: KRAS inhibitor + SHP2/EGFR/CDK4/6 inhibitors.

· Dual-target drug design.

· AI-driven molecular design and conformation simulation.

· Synthetic lethality exploration.

V. Future Outlook and Aladdin Scientific Support

KRAS has evolved from an "undruggable" target to one with multiple approved inhibitors — a milestone in targeted therapy history. With evolving design principles and chemical tools, the precision inhibition + combination strategy for different KRAS mutations is maturing.

Future Directions:

· Pan-conformation inhibitors (bind both ON/OFF states).

· KRAS PROTACs and degraders.

· AI-based drug discovery platforms.

· Personalized combination regimens.

· Targeting upstream/downstream nodes (e.g., RAF, ERK, PI3K).

Recommended Research Reagents from Aladdin:

Aladdin offers comprehensive reagent support for KRAS and RAS pathway studies, including but not limited to:

· KRAS proteins and antibodies.

· RAS pathway agonists/inhibitors (e.g., EGFR, PI3K inhibitors).

· Western blot kits (e.g., RIPA lysis buffer, BCA protein assay kit).

· Functional assay kits: CCK-8 cell viability, Annexin V/PI apoptosis detection kits.

Aladdin continues to empower KRAS-targeted research and drug development by providing high-quality, traceable scientific products.

Aladdin：https://www.aladdinsci.com/