Improved Synthesis of New FDA-Approved Treatment for KRAS G12C Mutation in Non-small Cell Lung Cancer

Full text of DOI:10.1021/acsmedchemlett.1c00330

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Patent Highlight
Improved Synthesis of New FDA-Approved Treatment for KRAS
G12C Mutation in Non-small Cell Lung Cancer
Robert B. Kargbo*
Cite This: https://doi.org/10.1021/acsmedchemlett.1c00330
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cause of most cancers. Mutations in the RAS oncogene are the
most common activating mutation, which is associated with the
development of cancerous tumors in human. The RAS gene
family consists of three isoforms: KRAS, HRAS, and NRAS.
However, 85% of RAS-driven cancers are caused by mutations in
the KRAS isoform. The inhibition of KRAS mutant protein has
been targeted as a potential therapeutic for cancer, which until
now has been challenging for finding a reliable KRAS mutant
cancer therapy. Among the KRAS mutant tumors, 80% of all
oncogenic mutations occur within codon 12, with G12C as the
actionable biomarker in NSCLC.
Important Compound Classes.
As shown in Scheme 1, AMG 510 was prepared from an
improved, efficient, and scalable process. Amide 1 reacted with
oxalyl chloride to give intermediate 2, which was carried through
Step 1b to give a DCM solution of intermediate 3 that was not
isolated but used directly in the next step. Urea compound 3
cyclized under basic condition to give rac-dione compound 4
(atropisomers) in 41% yield over two steps. Chiral separation
was carried out by reacting (+)-2,3-dibenzoyl-D-tartaric acid
with rac-dione 4 in 2-MeTHF warmed to 75 °C until the mixture
was fully dissolved and eventually cooled to 20 °C, which led to
solids of M-dione compound 5M in 37% yield over two steps.
Compound 5 was treated with phosphoryl chloride and N,N-
diisopropylethylamine (DIPEA) in toluene followed by (S)-1-
boc-3-methylpiperazine, which afforded pipazoline 6 in 66%
yield. Compound 6 was cross coupled under palladium catalyzed
conditions with boroxine 6A, which gave the biaryl compound 7
in 80% yield. Charcoal filtration removed residual palladium and
was followed by boc-deprotection reaction that afforded
compound 8 in 94% yield. Treatment with acryloyl chloride
gave crude 9A, which was purified to afford pure AMG 510.
Biological Assay and Patients’ Enrollment. Cellular
phosphorylated extracellular signal-regulated kinase (pERK)
assay for evaluation of serum concentration after dose
administration. The first patient was enrolled on August 27,
2018, and by July 17, 2019 76 patients were enrolled and 34 had
NSCLC. A total of 45 patients enrolled in the escalation cohort
Title. Improved Synthesis of KRAS G12C Inhibitor
Compound
Patent Publication Number. WO 2021/097207 A1 and
WO 2020/232130 A1
Publication Date. May 20, 2021 and November 19, 2020
Priority Application. 62/935,515, 62/847,862, 62/867,747
Priority Date. November 14, 2019; May 14, 2019; June 27,
2019 US.
Inventors. Corbett, M. T.; Caille, S.; Henary, H.; Lipford, J.
R.; Cee, V. J.
Assignee Company. Amgen Inc. [US/US]; One Amgen
Center Drive, Thousand Oaks, California 91320-1799 (US).
Disease Area. Cancer
Biological Target. KRAS G12C Mutant
Summary. The present Patent Highlight showcases the
improved, efficient, and scalable process to prepare the KRAS
G12C inhibitor AMG 510 (compound 9). AMG 510 (Lumakras
and Sotorasib the generic name) is the first ever FDA approved
drug that inhibits KRAS, a cancer target that has been termed
“undruggable” even after over 40 years of cancer research. AMG
510 is approved for KRAS G12C-mutated non-small cell lung
cancer (NSCLC), requiring a daily 960 mg dose. Consequently,
an efficient synthesis is desirable to provide a timely scale-up of
the drug to fulfill increased anticipated market demands.
Furthermore, this report may spur the investigation of
structure-based design efforts that could facilitate the discovery
of enhanced potency, permeability, solubility, and oral
bioavailability for derivatized AMG 510.
Received: June 11, 2021
Cancer is one of the deadliest diseases of the 21st century and
the second leading cause of death worldwide. Genetic mutations
can alter the proper expression and function of genes and
proteins that are vital to cell growth, proliferation, and
differentiation, which have been identified as the predominant
Published XXXX by American Chemical
Society
https://doi.org/10.1021/acsmedchemlett.1c00330
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
A

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Patent Highlight
4. Veluswamy, R.; Mack, P. C.; Houldsworth, J.; Elhouly, E.;
Hirsch, F. R. J. Mol. Diagn. 2021, 23, 507.
Scheme 1. Synthetic Steps in the Manufacture of AMG 510
5. Xie, M.; Xu, X.; Fan, Y. Front. Oncol. 2021, 11, 672612.
6. Erlanson, D. A.; Webster, K. R. Curr. Opin. Chem. Biol.
2021, 62, 101.
AUTHOR INFORMATION
Corresponding Author
■
Robert B. Kargbo − Usona Institute, San Luis Obispo,
California 93401-7337, United States; orcid.org/0000-
0002-5539-6343; Email: kargborb@gmail.com
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.1c00330
Notes
The author declares no competing financial interest.
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was originally published on July 7, 2021, with an error
in the AMG 510 structure. The corrected version was reposted
on July 9, 2021.
with daily doses of 180, 360, 720, and 960 mg; 31 patients
enrolled in the 960 mg expansion cohort.
Biological Data. The pharmacokinetic (PK) profile of
compound 9 (AMG 510), 960 mg oral total daily dose, including
patients with NSCLC and colorectal cancer (CRC) is as follows:
maximum serum concentration (Cmax) 7.5 μg/mL (98.3%), area
under the curve (AUC) 65.3 h·μg/mL (81.7% and elimination
half-life (t1/2,z) 5.5 h (1.8). The table below shows the efficacy of
AMG 510 in patients with NSCLC, where PR = partial response;
SD = stable disease; PD = progressive disease; Evaluated
patients = patients with measurable treatment response; n =
number of adverse effects; N = number of patients receiving
drug; RECIST = Response Evaluation Criteria In Solid Tumors.
aEvaluation of response is based on modified RECIST 1.1
criteria. bPR or SD at week 6.
Recent Review Articles.
1. Erlanson, D. A.; Webster, K. R. Curr. Opin. Chem. 2021,
62, 101.
2. Zhao, Y.; Xue, J. Y.; Lito, P. Cancer Discov 2021, 11, 17.
3. Mallapelle, U.; Passiglia, F.; Cremolini, C.; Reale, M. L.;
Pepe, F.; Pisapia, P. et al.Eur. J. Cancer 2021, 146, 74.
B
https://doi.org/10.1021/acsmedchemlett.1c00330
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX