Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS^G12C Inhibitor

Abstract

A commercial process to manufacture sotorasib (AMG 510), a first-in-class KRASG12C inhibitor, is described. Development efforts focused on rendering a fit-for-purpose early-phase route into a viable long-term commercial process through the reduction of side reactions to improve yield and product quality, as well as reducing cycle times of crystallization processes by improving particle properties and filtration times. These improvements were key to ensuring clinical supply and commercial launch. The final route consists of five synthetic operations from starting material M-1, including a telescoped two-step sequence, and a final form-setting crystallization.

Hindered Biaryl Bond Construction and Subsequent Diastereomeric Crystallization to Produce an Atropisomeric Covalent KRASG12C Inhibitor ARS-2102

“…The finding with EtOH as a solvent was further validated on a 2 g scale, affording a slightly higher 96:4 dr, which certainly has the potential of further optimization and incorporation into future campaigns. It is noteworthy that a similar approach was successfully realized by Amgen chemists for the synthesis of AMG-510 (Sotorasib), and an elegant atroposelective dynamic kinetic resolution of MRTX1719 was recently disclosed by Mirati …”

CMC development of [14C]-labeled sotorasib for the conduct of microtracer human ADME study

“…6 to provide the desired HSA [ 14 C]-1 with 98.1% radiochemical purity. The approach to synthesize [ 14 C]-1 from [ 14 C]-5 uses the same fundamental chemical transformations as the synthesis of unlabeled 1 (Zhang et al 2022) and therefore provided material with an equivalent The HSA [ 14 C]-1 was produced with a specific activity of 99.3 µCi/mg. With the target clinical dose of 720 mg and a maximum allowed radiolabeled dose of 1 µCi for hADME microtracer study, the target specific activity level of [ 14 C]-1 clinical DS was 1.4 nCi/mg, requiring a dilution of HSA with unlabeled 1 at a ratio of approximately 1:70,000.…”

Synthesis of Adagrasib (MRTX849), a Covalent KRASG12C Inhibitor Drug for the Treatment of Cancer

“…Kirsten rat sarcoma viral oncogene homologue (KRAS) is the notorious oncogene with the highest mutation rate among all cancers specifically associated with the top three most fatal cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) . Furthermore, KRAS has been considered as a challenging therapeutic target, famously designated as “undruggable”, and historically has had limited therapeutic options , until recent discovery of sotorasib (AMG510) and adagrasib (MRTX849, 1 in Scheme ) as drugs targeting the G12C variant. Adagrasib ( 1 ) is a highly selective and potent covalent KRAS G12C inhibitor, which has recently been approved as a monotherapy drug and is being evaluated in a combination therapy in patients with advanced KRAS G12C -mutated solid tumors. − Adagrasib ( 1 ) was reported to show only mild side effects when combined with the immunotherapy drugs .…”