Zidesamtinib (NVL-520, Jideytro): FDA Approval for ROS1-Positive NSCLC
Zidesamtinib (NVL-520, marketed as Jideytro) was approved by the FDA on July 22, 2026 for adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who have received a prior ROS1 tyrosine kinase inhibitor (TKI) (Figure 1) [1]. The approval came seven days after GSK completed its acquisition of Nuvalent, which discovered the compound, at an aggregate equity value of approximately $10.6 billion [2].
Figure 1 Structure of zidesamtinib (NVL-520, Jideytro), a macrocyclic, TRK-sparing ROS1 inhibitor.
Why ROS1 Needed Another Inhibitor
ROS1 rearrangements are found in 1% to 2% of NSCLC. Crizotinib and entrectinib give good initial responses, but three problems recur:
Kinase-domain point mutations occur in 38% to 53% of patients who progress on crizotinib, most often the solvent-front substitution G2032R.
The CNS is the only site of progression in 47% of patients.
Later agents that cover G2032R also inhibit TRK, the family of TRKA, TRKB and TRKC [3].
TRKB is the receptor for brain-derived neurotrophic factor. Its inhibition in the CNS causes dizziness, cognitive disturbance and neuropathic pain, which can limit dosing. Zidesamtinib was designed to address all three problems [4].
Retrosynthetic Analysis of Zidesamtinib with ChemAIRS®
Zidesamtinib is a macrocyclic, TRK-sparing ROS1 inhibitor. Its synthesis requires several heteroaromatic fragments to be joined around a macrocycle while the benzylic stereochemistry is controlled.
ChemAIRS® proposed several routes. Two are described here. Route 1 follows chemistry reported for a related Nuvalent compound and extends it to the target. Route 2 uses a different fragment assembly and macrocyclization, and has eight steps with a longest linear sequence (LLS) of six.
Route 1: ChemAIRS® Retrosynthesis Based on Nuvalent’s Reported Chemistry
Scheme 1 ChemAIRS® route to zidesamtinib (NVL-520) following chemistry reported for a related Nuvalent compound.
The first proposal follows the general strategy reported in the patent literature for a related Nuvalent compound (Scheme 1) [5]. It starts from a commercial diiodotriazole and reaches intermediate 7a (Scheme 1) in five linear steps. The benzylic stereocenter comes from a commercial chiral benzylic alcohol. This fragment is converted to a cyclic boronic acid derivative and joined by Suzuki coupling.
The remaining steps are nitro-group reduction, intramolecular Mizoroki–Heck macrocyclization and SEM deprotection. ChemAIRS® then adds a final methylation to give the target.
This route is a useful reference because the strategy has precedent. The sequence to zidesamtinib itself is a proposal, and it should not be read as an experimentally reproduced synthesis unless experimental data are available.
Route 2: ChemAIRS's 8-Step Retrosynthetic Strategy for Zidesamtinib Synthesis
The second ChemAIRS® proposal outlines an eight-step route with a longest linear sequence (LLS) of six steps. This route differs from Route 1 in both fragment assembly and macrocyclization (Scheme 2).
Scheme 2 Eight-step ChemAIRS® route to zidesamtinib (NVL-520), with a longest linear sequence of six steps
Commercial heterocycles 3a and 3b undergo a microwave-assisted vicarious nucleophilic substitution to give 4a. Two Suzuki–Miyaura couplings then install the fluorinated aryl fragment 4b and the protected 2-aminopyridine 5b, which gives the key ketone 6a. Fragment 5b is prepared in two steps from the commercial 2-aminopyridine derivative 1b.
CBS reduction of ketone 6a sets the stereocenter and gives the chiral alcohol 7a (Scheme 2). Intramolecular nucleophilic aromatic substitution (SNAr) then closes the macrocycle to give 8a, and Boc deprotection delivers zidesamtinib. The last three steps use no transition metal.
ChemAIRS® Condition Search and Impurity Prediction for Zidesamtinib Synthesis
ChemAIRS® Condition Searchwas used to look for alternative conditions for the final Boc deprotection. The query accounted for the macrocyclic ether and the aryl fluoride, which may raise compatibility concerns under some conditions. The results can be screened if needed (Figure 2).
Figure 2 ChemAIRS® Condition Search results for the final Boc deprotection of 8a (Scheme 2)
Impurity prediction is most useful for reactions with no direct precedent. Applied to the macrocyclization of 7a, it flagged an intermolecular coupling product, a dimer formed from two molecules of starting material (Figure 3). Running the reaction at high dilution in the indicated solvent is one way to favour intramolecular ring closure over this pathway.
Figure 3 ChemAIRS® Impurity Prediction for the macrocyclization of 7a (Scheme 2), with the intermolecular dimer as the competing product.
What Is ChemAIRS®? AI-Powered Retrosynthesis Platform
ChemAIRS® is a computer-aided synthesis planning (CASP) platform that proposes retrosynthetic routes to existing and novel molecules, ranking them by feasibility and by access to readily available building blocks. Its Retrosynthesis module combines machine learning with encoded chemical logic, and every step remains open to interrogation, so chemists can troubleshoot a disconnection or explore alternative methodology rather than accept a route as given. The platform is built to extend a chemist's strategic reach, not to substitute for it.
ChemAIRS® Route Planning for Zidesamtinib: From Reported Chemistry to Alternative Routes
The two proposed routes to zidesamtinib illustrate different approaches to assembling its macrocyclic scaffold. Route 1 builds on reported chemistry for a related Nuvalent compound, while Route 2 offers an alternative eight-step sequence with a longest linear sequence of six steps. Its final three transformations—CBS reduction, intramolecular SNAr macrocyclization, and Boc deprotection—establish the stereogenic center, close the macrocycle, and reveal the 2-aminopyridine functionality without requiring a transition-metal catalyst.
ChemAIRS® Condition Search identified alternative conditions for the final deprotection, while Impurity Prediction highlighted a potential intermolecular coupling product during macrocyclization of 7a. These analyses provide specific considerations for reaction screening and experimental planning.
Although Route 2 remains a proposal requiring experimental validation, its comparison with the precedent-based Route 1 demonstrates how ChemAIRS® can explore alternative disconnections and synthetic sequences for the same target. The resulting routes give chemists different starting points for evaluating fragment assembly, macrocyclization, and reaction conditions during synthetic route development.
Curious what ChemAIRS® Retrosynthesis can do for your chemistry?
References
FDA approves zidesamtinib for ROS1-positive non-small cell lung cancer. U.S. Food and Drug Administration. Updated July 24, 2026. Accessed July 27, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zidesamtinib-ros1-positive-non-small-cell-lung-cancer
GSK completes acquisition of Nuvalent, Inc. Press release. GSK plc. July 15, 2026. Accessed July 27, 2026. https://www.gsk.com/en-gb/media/press-releases/gsk-completes-acquisition-of-nuvalent-inc/
Desilets A, Repetto M, Yang S-R, Drilon A. Targeting ROS1 rearrangements in non–small cell lung cancer: current insights and future directions. Cancer. 2025;131(suppl 1):e35784. https://doi.org/10.1002/cncr.35784
Drilon A, Horan JC, Tangpeerachaikul A, et al. NVL-520 is a selective, TRK-sparing, and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations. Cancer Discov. 2023;13(3):598-615. https://doi.org/10.1158/2159-8290.CD-22-0968
Horan JC, Soglia JR, inventors; Nuvalent, Inc., assignee. Heteroaromatic macrocyclic ether compounds. International patent WO 2024/036098 A1. February 15, 2024.