其他
杰克说药丨用KRAS-G12C抑制剂治疗癌症,Amgen为何最早拥有第一个临床候选化合物?
杰克说药是著名药史专家Jie Jack Li(李杰)教授专为同写意打造的药林外史精品专栏,将讲述一个个药物发现背后的故事。李杰教授现为上海睿智的副总裁,先后出版了30本有机和药物化学方面的书籍以及药物发现史,其中10本与诺奖得主E. J. Corey合作完成。其《Blockbuster Drugs》一书获 2015 Alpha Sigma Nu Science Book 奖,并被翻译成中文出版,深受欢迎。
开设写意专栏,请联系同写意秘书处(微信号tongxieyimishuchu)
首先要弄明白的是,
什么是KRAS?
什么是 G12C?
为什么KRAS-G12C抑制剂会引起公众的关注?
—KRAS-G12C Inhibitors to Treat Cancer
Jie Jack Li, Vice President of Discovery Chemistry at Shanghai ChemPartner
On October 25, 2020, Mirati Therapeutics, a small biotech company in San Diego, announced their preliminary phase I/1b and II results of their cancer drug adagrasib (1). It showed deep and durable anti-tumor activity in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other solid tumors, providing renewed hope for patients that harbor a KRAS G12C mutation. It is compelling for a 45% confirmed objective response rate for adagrasib (1) as a monotherapy in advanced NSCLC. The news electrifying the drug industry and everyone, including the cancer patients, doctors, researchers, and investors alike, is getting excited:One wonders,what is KRAS?what is G12C?Why a KRAS-G12C inhibitor is generating so much publicity?RAS is an abbreviation for Rat Sarcoma. RAS oncogene, on the other hand, was actually the first human oncogene discovered by Robert Weinberg in the 1982. Quite ironically, when Michael Bishop and Harold Varmus received the Nobel Prize in 1989 for their “discovery of cellular origin of retroviral oncogenes”, it was widely believed that Robert Weinberg should have shared the Prize with them. Not only did Weinberg discover RAS, the first human oncogene, he also made significant contributions to the discovery of tumor suppressor gene Rb.1
G12C in KRAS-G12C mutations indicates that the glycine amino acid (Gly, G) at codon-12 of the KRAS protein has mutated to a cysteine amino acid (Cys, C). This is consequential because cysteine will be employed as the reactive nucleophile thiol (–SH) to form covalent bonds with the warheads of targeted covalent KRAS-G12C inhibitors. Mirati’s adagrasib (1) is one of them.RAS gene family are the most frequently mutated oncogenes in human cancers. Mutant RAS appears in 90% of pancreatic, 45% of colon, and 35% of lung cancers. Among the three Ras genes, Kirsten-RAS (KRAS) is the most frequently mutated isoform (86%), therefore, of the greatest interest. The other two isoforms neuroblastoma-RAS (NRAS, 11%) and Harvey-RAS (HRAS, 3%) are of less interest. With regard to the KRAS proteins, there are several mutations. The KRAS-G12C mutation, in particular, predominates in NSCLC (45–50% of mutant KRAS-G12C). On the other hand, KRAS-G12D (where glycine at codon-12 has mutated to aspartate), is important in pancreatic cancer (61%), colon cancer (42%), and NSCLC (22%).2 Because the importance of the RAS protein in oncology, much effort has been devoted to find inhibitors of this valuable drug targets ever since Weinberg discovered the RAS oncogene forty years ago. But first thirty years of drug discovery effort in this field was completely fruitless because RAS’s lack of deep pockets for binding of small molecule inhibitors. Amgen chemists compared the surface of the RAS protein to the surface of the Death Star in the movie Star Wars. It is not that surprising that RAS was considered a “undruggable” target although it is implicated in many cancers. Recent successes with RAS direct inhibitors, KRAS-G12C inhibitors in particular, are a testimony of scientistsʹ ingenuity and perseverance. The breakthrough came when Prof. Kevan Shokat at the University of California at San Francisco published his landmark paper in 2013. In his Nature paper, Shokat described a series of KRAS-G12C inhibitors that allosterically control guanosine triphosphate (GTP) affinity and effector interactions.3 His team chose to use covalent inhibitors to tackle this tough target, specifically the switch-II pocket (S-IIP). The warheads that they used included disulfides, vinyl sulfonamides, and acrylamides (e.g., acrylamide 2). All of these warheads reacted with the cysteine amino acid at the 10 position to form a covalent S–C bond.
Today, we have learned enough to understand that targeted covalent inhibitors have many advantages in drug discovery. They include:· Applicability to some “undruggable” targets, obviously it is the case for KRAS-G12C inhibitors;· High potency;· Extended duration of action; and· Ability to directly measure target.
A biotech company Wellspring Biosciences that Shokat helped to found capitalized his revolutionary discovery. They came up with a covalent KRAS-G12C-specific inhibitor ARS-853 (3), which was the first compound to show cellular activities. A more rigid quinoline-containing analogue ARS-1620 (4), disclosed in 2018, was one of the first covalent KRAS-G12C-specific inhibitors that were active in vivo.4 Eventually, Wellspring and Janssen collaborated to bring ARS-3248 (JNJ-74699157, structure not disclosed thus far) to clinical trials in July 2019. But that was the third of such drugs that went to clinical trials. Despite starting first, Wellspring lagged behind both Amgen and Mirati.In April 2019 at the ACS meeting in Orlando, Amgen announced their drug candidate AMG 510 (sotorasib, 5), a covalent KRAS-G12C-specific inhibitor started its first-in-human trials in patients with advanced KRAS-G12C mutant solid tumors.5a That was the first of this class of drugs that went to clinical trials. The whole drug industry was stunned.Where did they come from?Why did Amgen have the first clinical candidate before everyone else?It turned out that the Amgen team in Thousand Oaks, California already had abundant experience with targeted covalent inhibitors previously when they worked on epidermal growth factor receptor (EGFR) inhibitors. Collaboration with a Berkeley biotech company Carmot Therapeutics helped Amgen screen 100,000 unpurified compounds in a matter of two and half years. More excitingly, in July, 20195b Amgen reported their Phase I clinical trial outcome of their first-in-class covalent KRAS-G12C-specific inhibitor AMG 510 (sotorasib, 5): 54% of 13 evaluable NSCLC patients experienced a partial response (PR) at the target dose of 960 mg in the ongoing Phase 1 study. Meanwhile, 46% of patients had stable disease for a disease control rate of 100% at the target dose. The FDA granted AMG 510 (sotorasib, 5) fast track designation for previously treated metastatic NSCLC with KRAS-G12C mutation. The KRAS-G12C drug target, the previously “undruggable” target has now become one of the most popular cancer targets.Hot on the heel of AMG 510 (sotorasib, 5), Mirati and Array Biopharma also announced their covalent KRAS-G12C-specific inhibitor MRTX849 (1)6 went to phase I clinical trials in the summer of 2019. As a matter of fact, Mirati and Array already had a pretty good drug candidate MRTX1257 (6) one year ago already. However, they decided to optimize a bit further to have a more ideal drug to go to clinical trials. Now with the clinical readings out for MRTX849 (1), their decision has been proven wise.
Here is the answer to the question:Why all the excitement?In drug discovery, some milestones are more important than others. When a drug using certain mechanism of action (MoA) has been proven efficacious in phase II clinical trials, we consider that particular MoA has achieved proof-of-concept (PoC). Historically, mechanism of action with proof-of-concept has an exponentially highly probability of succeeding in going to the market than MoA without PoC. That, is good for the patients, doctors, and investors.We only have scratched the surface of the KRAS-G12C inhibitors. Their discovery is a treasure trove from which we can learn valuable lessons. But that is for another blog in the future. References1. Weinberg. Robert A. Racing to the Beginning of the Road, The Search for the Origin of Cancer, W. H. Freeman and Company: New York, NY, 1998.2. Stephen, A. G.; Esposito, D.; Bagni, R. K.; McCormick, F. Cancer Cell 2014, 25, 272–281.3. Ostrem, J. M.; Peters, U.; Sos, M. L; Wells, J. A.; Shokat, K. M. Nature 2013, 503, 548–551.4. (a) Janes, M. R.; Zhang, J.; Li, L.-S.; Hansen, R.; Peters, U.; Guo, X.; Chen, Y.; Babbar, A.; Firdaus, S. J.; Darjania, L.; et al. Cell 2018, 172, 578–589. (b)5. (a) Fell, J. B.; Fischer, J. P.; Baer, B. R.; Ballard, J.; Blake, J. F.; Bouhana, K.; Brandhuber, B. J.; Briere, D. M.; Burgess, L. E.; Burkard, M. R.; et al. ACS Med. Chem. Lett. 2018, 9, 1230–1234. (b) Anon, Cancer Discov.2019, 9, 988–989.6. Fell, J. B.; Fischer, J. P.; Baer, B. R.; Blake, J. F.; Bouhana, K.; Briere, D. M.; Brown, K. D.; Burgess, L. E.; Burns, A. C.; Burkard, M. R.; et al. 2020, 63, 6679–6693.
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