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Integrating Human Insight with AI: Retrosynthetic Exploration of Surzetoclax (ABBV-453)
Drug Discovery & Development, Oncology Drug Discovery, Synthetic & Medicinal Chemistry, AI in Drug Discovery, Human–AI Collaboration Ganna Posternak Drug Discovery & Development, Oncology Drug Discovery, Synthetic & Medicinal Chemistry, AI in Drug Discovery, Human–AI Collaboration Ganna Posternak

Integrating Human Insight with AI: Retrosynthetic Exploration of Surzetoclax (ABBV-453)

Using ChemAIRS, we explored synthetic pathways to AbbVie’s Surzetoclax (ABBV-453), a highly complex, next-generation BCL-2 inhibitor weighing nearly 1000 Da with multiple fused tricyclic and macrocyclic rings. In High-Risk Retrosynthesis mode, ChemAIRS showcased its ability to navigate this molecular complexity. Guided by human insight, the AI-driven retrosynthesis platform delivered a streamlined, convergent, and experimentally executable synthesis, highlighting the power of human-AI collaboration in modern drug discovery.

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ChemAIRS-Driven Retrosynthesis of Elironrasib (RMC-6291): A Next-Gen KRAS-G12C(ON) Inhibitor_EP20
Oncology Drug Discovery, Synthetic & Medicinal Chemistry, Artificial Intelligence in Pharma, Clinical Trials & Therapeutics, Pharmaceutical Innovation My Cao Oncology Drug Discovery, Synthetic & Medicinal Chemistry, Artificial Intelligence in Pharma, Clinical Trials & Therapeutics, Pharmaceutical Innovation My Cao

ChemAIRS-Driven Retrosynthesis of Elironrasib (RMC-6291): A Next-Gen KRAS-G12C(ON) Inhibitor_EP20

The ChemAIRS platform successfully reconstructed a 25-step synthetic route to Revolution Medicines' groundbreaking KRAS inhibitor, elironrasib (RMC-6291). This next-generation therapeutic leverages a sanglifehrin-inspired macrocycle to form a stable tri-complex with KRAS-G12C(ON) and cyclophilin A (CypA), achieving exceptional selectivity through conformational rigidity.

Key ChemAIRS contributions:

  • Modular retrosynthesis: Deconstructed the macrocycle into two manageable fragments

  • Supply chain optimization: Identified commercially available starting materials

  • Risk mitigation: Flagged potential side reactions for synthetic planning

  • Route validation: Closely mirrored Revolution Medicines' published strategy

By combining macrocyclic drug design with AI-driven synthesis planning, ChemAIRS demonstrates how computational tools can accelerate the development of complex targeted therapies.

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