Silevertinib

 

Silevertinib

CAS 2607829-38-7

MF C30H30ClFN6O2 MW561.0 g/mol

(E)-N-[4-(3-chloro-2-fluoroanilino)-7-[2-[(1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl]quinazolin-6-yl]-4-morpholin-4-ylbut-2-enamide

(2E)-N-[4-(3-chloro-2-fluoroanilino)-7-{[(1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl}quinazolin-6-yl]-4-(morpholin-4-yl)but-2-enamide
epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, BDTX-1535, BDTX 1535, CANCER, Glioblastoma, Black Diamond Therapeutics, RP9F537KVY

Silevertinib is an investigational new drug that is being evaluated by Black Diamond Therapeutics for the treatment of glioblastoma and non-small cell lung cancer.^[1] It is a EGFR protein tyrosine kinase inhibitor.^[1][2]

Silevertinib (formerly known as BDTX-1535) is an investigational, orally bioavailable, fourth-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed by Black Diamond Therapeutics. It is specifically engineered to be brain-penetrant and to target a broad spectrum of both classical and non-classical EGFR mutations, as well as resistance mutations, while sparing wild-type EGFR to reduce side effects.

Silevertinib is an orally bioavailable, brain penetrating, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, silevertinib selectively targets, irreversibly binds to, and inhibits the activity of various EGFR alterations and mutations, including certain intrinsic and acquired resistance mutations. This prevents EGFR-mediated signaling in susceptible tumor cells. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.

Mechanism of Action

Silevertinib works by selectively and irreversibly binding to mutated EGFR receptors. EGFR is a receptor tyrosine kinase that, when mutated, triggers uncontrolled cell division and tumor vascularization. By shutting down this signaling cascade, silevertinib induces tumor cell death and inhibits further growth.

A major clinical advantage of the drug is its ability to cross the blood-brain barrier, allowing it to target central nervous system (CNS) tumors and brain metastases that many traditional therapies fail to reach.

Target Indications & Clinical Data

Silevertinib is primarily being studied for two aggressive types of cancer:

• Non-Small Cell Lung Cancer (NSCLC): It targets frontline patients with classical and over 50 non-classical EGFR driver mutations, as well as patients who have developed the acquired C797S resistance mutation from prior treatments. Phase 2 clinical trial data presented at the American Society of Clinical Oncology (ASCO) 2026 Annual Meeting showcased robust efficacy:
  • Objective Response Rate (ORR): 60% in treatment-naïve patients.
  • CNS Response Rate: An impressive 86% intracranial ORR in patients presenting with brain metastases.
  • Disease Control Rate (DCR): 91%.
• Glioblastoma Multiforme (GBM): In May 2026, a randomized Phase 2 trial was initiated for newly diagnosed patients with EGFRvIII-positive, MGMT-negative glioblastoma, evaluating silevertinib in combination with temozolomide.

Safety Profile & Side Effects

The adverse events of silevertinib are consistent with the broader class of EGFR inhibitors. The most frequently reported treatment-related adverse events (TRAEs) include:

• Rash
• Diarrhea
• Stomatitis (mouth sores)
• Paronychia (nail bed inflammation)

While a high percentage of patients (up to 77–84%) require dose reductions to manage these side effects, data shows that 86% of responding patients maintained or deepened their clinical response even after dropping to a lower dose. The treatment discontinuation rate remains low at roughly 9–14%, indicating the drug is manageable for long-term therapy.

Regulatory Status

As an investigational drug, silevertinib is not yet approved for commercial use by global regulatory agencies. However, the manufacturer anticipates regulatory feedback from the US FDA regarding its registration pathway for first-line NSCLC therapy.

• OriginatorBlack Diamond Therapeutics
• Class2 ring heterocyclic compounds; Amides; Amines; Aniline compounds; Antineoplastics; Halogenated hydrocarbons; Morpholines; Quinazolines; Small molecules
• Mechanism of ActionErbB receptor antagonists
• Phase IIGlioblastoma
• Phase I/IINon-small cell lung cancer
• Phase 0Glioma
• 06 Aug 2026Black Diamond Therapeutics anticipates regulatory feedback from the US FDA on registration path of silevertinib for Non-small cell lung cancer (First-line therapy) in the fourth quarter of 2026 (Black Diamond pipeline, May 2026)
• 02 Jun 2026Efficcay and adverse event data from phase I/II trial in Non-small cell lung cancer presented at the 62nd Annual Meeting of the American Society of Clinical Oncology (ASCO-2026)
• 21 May 2026Efficacy and adverse events data from a phase I/II trial in Non small cell lung cancer released by Black Diamond Therapeutics

SYN

• BDTX-1535 Goes after Osimertinib ResistancePublication Name:Cancer DiscoveryPublication Date:2021-12-01PMID:34702733DOI:10.1158/2159-8290.cd-nb2021-0395
• Further characterization of a DNA polymerase activity in mouse sperm nucleiPublication Name:Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein SynthesisPublication Date:1976-10-04PMID:10003DOI:10.1016/0005-2787(76)90342-7

PAT

[WO2021030711]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021030711&_cid=P21-MU6CBO-49598-1

Example 33. Synthesis of Compound No. 37 ((E)-N-(4-((3-chloro-2-fluorophenyl)amino)-7-(((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)-4-morpholinobut-2-enamide)

PAT

WO2026064728

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=2A0850BB19B29C599F589233A4E61A49.wapp2nB?docId=WO2026064728&_cid=P21-MU6C38-37561-1

PAT

US20220298120

https://patentscope.wipo.int/search/en/detail.jsf?docId=US375116378&_cid=P21-MU6C60-41372-1

Example 33. Synthesis of Compound No. 37 ((E)-N-(4-((3-chloro-2-fluorophenyl)amino)-7-(((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)-4-morpholinobut-2-enamide)

Step 1. To a solution of (E)-4-bromobut-2-enoic acid (5.00 g, 30.3 mmol) and dimethylformamide (22.2 mg, 303 umol) in dichloromethane (20 mL) was added (COCl) 2 (3.85 g, 30.3 mmol) dropwise at 0° C. under N 2. The mixture was stirred at 0-25° C. for 4 h. On completion, the reaction mixture was concentrated in vacuo to give (E)-4-bromobut-2-enoyl chloride (5.8 g, crude) as a yellow oil.

Step 2. To a solution of N4-(3-chloro-2-fluoro-phenyl)-7-[2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl]quinazoline-4,6-diamine (4.00 g, 9.81 mmol) and triethylamine (2.98 g, 29.4 mmol) in dichloromethane (70 mL) was added a solution of (E)-4-bromobut-2-enoyl chloride (3.60 g, 19.6 mmol) in dichloromethane (15 mL) dropwise at 0° C. and the mixture was stirred at 0° C. for 10 min. On completion, the reaction mixture was concentrated under vacuum to give (E)-4-bromo-N-(4-((3-chloro-2-fluorophenyl)amino)-7-4(1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)but-2-enamide (5.44 g, crude) as a yellow solid, which was used for next step directly. m/z ES+ [M+H] + 556.0

Step 3. A mixture of (E)-4-bromo-N-[4-(3-chloro-2-fluoro-anilino)-7-[2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl]quinazolin-6-yl]but-2-enamide (5.44 g, 9.80 mmol), morpholine (1.71 g, 19.6 mmol), triethylamine (992 mg, 9.80 mmol) in dichloromethane (1.5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 25° C. for 12 hrs under N 2 atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase flash [acetonitrile/(0.1% formic acid in water), 0% to 90%] to give 2.8 g crude product. Then it was purified by Prep-HPLC [column: Waters Xbridge BEH C18 250*50 mm*10 um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; B %: 35%-55%, 22 min] to give 2.2 g crude product. Then the crude product was triturated with EA/petroleum ether=5/1 (200 mL) twice to give (E)-N-[4-(3-chloro-2-fluoro-anilino)-7-[2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl]quinazolin-6-yl]-4-morpholino-but-2-enamide (1.84 g, 33% yield) as a yellow solid. m/z ES+ [M+H] + 561.3; 1H NMR (400 MHz, DMSO-d 6) δ 10.06 (s, 1H), 9.78 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 7.80 (s, 1H), 7.50 (s, 2H), 7.29 (t, J=7.6 Hz, 1H), 6.81 (td, J=5.6, 15.6 Hz, 1H), 6.45 (d, J=15.6 Hz, 1H), 3.65-3.60 (m, 4H), 3.17 (d, J=5.2 Hz, 2H), 3.11 (d, J=8.4 Hz, 1H), 2.93 (d, J=9.0 Hz, 1H), 2.46-2.38 (m, 6H), 2.26 (s, 3H), 1.98-1.90 (m, 1H), 1.38 (t, J=4.4 Hz, 1H), 1.03 (dd, J=4.0, 8.0 Hz, 1H).

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References

1.  "Silevertinib". AdisInsight. Springer Nature Switzerland AG. Retrieved 5 July 2026.
2.  Joshi H, Sheikh MS (August 2025). "Cell Death, Molecular Targeted Therapies, and Metabolic Reprogramming in EGFR-Mutant Lung Cancer". Cancers. 17 (17). Basel: 2791. doi:10.3390/cancers17172791. PMC 12427363. PMID 40940888.

PAT

• Polymorphs as erbb inhibitorsPublication Number:EP-4405350-A1Priority Date:2021-09-21
• Polymorphs as erbb inhibitorsPublication Number:US-2024425492-A1Priority Date:2021-09-21
• Polymorphs as erbb inhibitorsPublication Number:WO-2023049168-A1Priority Date:2021-09-21
• Method of treating cancers with alkyne substituted quinazoline derivativesPublication Number:WO-2022094464-A1Priority Date:2020-11-02
• Alkynyl quinazoline compoundsPublication Number:EP-4013749-A1Priority Date:2019-08-15
• Alkynyl quinazoline compoundsPublication Number:US-2022298120-A1Priority Date:2019-08-15
• Alkynyl quinazoline compoundsPublication Number:US-2026049063-A1Priority Date:2019-08-15
• Alkynyl quinazoline compoundsPublication Number:US-12435046-B2Priority Date:2019-08-15Grant Date:2025-10-07
• Alkynyl quinazoline compoundsPublication Number:EP-4013749-B1Priority Date:2019-08-15Grant Date:2026-03-11
• Alkynyl quinazoline compoundsPublication Number:WO-2021030711-A1Priority Date:2019-08-15

Clinical data
Other names	RVU-120
Identifiers
IUPAC name
CAS Number	2607829-38-7
PubChem CID	156071569
IUPHAR/BPS	13371
UNII	RP9F537KVY
KEGG	D13300
Chemical and physical data
Formula	C30H30ClFN6O2
Molar mass	561.06 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

///////////silevertinib, anax labs, epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, BDTX-1535, BDTX 1535, CANCER, Glioblastoma, Black Diamond Therapeutics, RP9F537KVY

#silevertinib, #anax labs, #epidermal growth factor receptor tyrosine kinase inhibitor, #antineoplastic, #BDTX-1535, #BDTX 1535, #CANCER, #Glioblastoma, #Black Diamond Therapeutics, #RP9F537KVY