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MLA Full: "The Reason Prescription Drugs Will Never Be Developed Fast!" YouTube, uploaded by SciShow, 9 March 2022, www.youtube.com/watch?v=KRZu6S4fdfs.
MLA Inline: (SciShow, 2022)
APA Full: SciShow. (2022, March 9). The Reason Prescription Drugs Will Never Be Developed Fast! [Video]. YouTube. https://youtube.com/watch?v=KRZu6S4fdfs
APA Inline: (SciShow, 2022)
Chicago Full: SciShow, "The Reason Prescription Drugs Will Never Be Developed Fast!", March 9, 2022, YouTube, 12:47,
https://youtube.com/watch?v=KRZu6S4fdfs.
Hank Green talks with us about why research and development make the prescription drug development process long... understandably.
Use code SCISHOW to get $5 off your delicious, healthy Magic Spoon cereal by clicking this link: https://magicspoon.thld.co/scishow_0322

It can potentially take decades for medications to reach pharmacy shelves, but why? We take a deep dive into the creation of a cancer treatment to explain the process.

Hosted by: Hank Green

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Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354961/
https://www.nature.com/articles/s41586-019-1694-1
https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug
https://www.cell.com/the-innovation/pdf/S2666-6758(20)30035-7.pdf
https://pubmed.ncbi.nlm.nih.gov/26739882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216832/
https://www.amgen.com/newsroom/press-releases/2021/01/amgens-investigational-kras-g12c-inhibitor-sotorasib-demonstrated-rapid-deep-and-durable-responses-in-previously-treated-patients-with-advanced-nonsmall-cell-lung-cancer
https://www.cell.com/cell/fulltext/S0092-8674(18)30041-2?_return
https://directorsblog.nih.gov/2018/02/13/kras-targeted-cancer-strategy-shows-early-promise/
https://www.science.org/content/article/two-new-drugs-finally-hit-undruggable-cancer-target-providing-hope-treatments

MOLECULE STRUCTURES

Compound 12 https://pubs.rsc.org/image/article/2020/MD/d0md00096e/d0md00096e-u5_hi-res.gif
ARS-853 https://pubs.rsc.org/image/article/2020/MD/d0md00096e/d0md00096e-u7_hi-res.gif
ARS-1620 https://pubs.rsc.org/image/article/2020/MD/d0md00096e/d0md00096e-u8_hi-res.gif
ARS-510 https://pubs.rsc.org/image/article/2020/MD/d0md00096e/d0md00096e-u10_hi-res.gif
MRTX849 https://pubs.rsc.org/image/article/2020/MD/d0md00096e/d0md00096e-u13_hi-res.gif

Images

https://www.storyblocks.com/video/stock/rack-focus-from-scientist-digital-tablet-pc-to-researcher-desk-working-on-a-computer-with-advanced-scan-bbej_kdjrjx32gd8i
https://www.istockphoto.com/photo/testing-drugs-and-vaccine-on-mice-gm1227553397-362087698
https://www.istockphoto.com/photo/laboratory-mouse-gm172267826-3711102
https://commons.wikimedia.org/wiki/File:Freezed_XRD.jpg
https://www.mdpi.com/1422-0067/21/18/6806/htm
https://www.istockphoto.com/vector/utility-knife-line-style-icon-design-gm1156138646-314996692
https://www.istockphoto.com/photo/scientist-carefully-carrying-matured-cell-to-another-plate-conducting-research-gm879831370-245197680
https://www.istockphoto.com/photo/medical-science-laboratory-with-diverse-multi-ethnic-team-of-biotechnology-gm1293772957-388051705
https://commons.wikimedia.org/wiki/File:KRAS_protein_3GFT.png
https://www.storyblocks.com/video/stock/abstrat-industrial-clock-gears-2-sw-amfntbk3z8wb2m
https://www.istockphoto.com/photo/skin-gm56961296-29923876
https://commons.wikimedia.org/wiki/File:Oncogenes_illustration.jpg
https://www.storyblocks.com/video/stock/macro-shot-of-lab-tech-placing-a-blood-sample-on-a-bightly-lit-microscope-slide-syvn75mkpkcdpmjki
https://www.istockphoto.com/photo/microscope-with-lab-glassware-gm909908830-250604421
https://commons.wikimedia.org/wiki/File:FDA_Sign_%26_Bldg_21_at_Entrance_(5204602349).jpg
https://www.istockphoto.com/photo/asian-senior-elderly-male-patient-consult-with-physician-nurse-at-nursing-home-care-gm1317922601-405208908
https://www.istockphoto.com/photo/efficient-pharmacy-operations-thanks-to-teamwork-gm1036131880-277355254
https://www.istockphoto.com/photo/this-is-how-i-get-through-the-day-gm1135088881-301842519
https://www.istockphoto.com/photo/theres-always-something-waiting-to-be-discovered-gm1027139762-275404932
https://www.istockphoto.com/photo/theres-always-something-waiting-to-be-discovered-gm1027139762-275404932
Thank you to Magic Spoon for sponsoring today’s episode!

Go to magicspoon.com/SciShow and use the code SciShow at checkout to get $5 off any order. [♪ INTRO] Creating a new medication takes years, and sometimes decades, of work. Sotorasib, a recently approved lung cancer drug, might seem super new, but it has a story starting with research in the 80s.

Medications like sotorasib had to take a long, difficult path through laboratory testing, clinical trials in people, and evaluation and approval by regulatory agencies before they reached doctors’ offices and store shelves. And once they’ve made that journey, they can finally help patients. Today, we want to peek behind the curtain a bit and look at one of the earliest phases of drug research, which can also feel the most secretive and mysterious: research and development, or R&D.

We can see all of the areas of R&D in practice by following the winding road to the creation of the medication sotorasib. The U. S.

Food and Drug Administration approved sotorasib in May 2021 for use under certain circumstances to treat lung cancer. Specifically, it targets cancers caused by a mutation in the gene KRAS, which is linked to about a quarter of non-small cell lung cancer cases. But first, we had to learn exactly what we were dealing with.

So this medication’s journey to being created started decades earlier with the first stage of R&D, the basic research phase. See, R&D involves working to increase how much we know about a subject and then finding new ways to apply that knowledge. To be considered research and development, that work needs to be new, have a creative and planned approach, and be reproducible by other people.

When it comes to scientific research, those qualities apply to three stages: First, basic research, which seeks a foundational understanding of something, applied research, which usually has a more specific or practical objective than basic research, and experimental development, which uses the basic and applied research to create a new product or improve something that’s already out there. So, to start, we had to get a foundational understanding of how the KRAS gene works a nd how mutations of it can lead to cancer. Our genes are written in the chemical code of life, DNA.

And when a cell needs to use a gene, it transcribes and translates the code into another chemical, amino acids. For example, cells use the KRAS gene to build K-Ras proteins. When there’s a mutation, or mistake, in the DNA, that can lead the cell to use the wrong amino acid when it’s building a protein.

About half of cancers linked to KRAS have G12C mutations. That means that the twelfth amino acid in the protein, which is normally glycine, is replaced by cysteine. And researchers have known about this mutation and its link to cancer for a long time.

KRAS was actually one of the first cancer-causing genes, or oncogenes, discovered in the early 1980s, around the same time as HRAS and NRAS. Each of these genes encodes a protein of the same name. As a group, they’re called “Ras proteins.” Healthy Ras proteins spend a lot of time inactive, not doing anything in the cell.

But a few supervisor proteins can activate them, and when activated, Ras proteins start directing lots of other cellular machinery to make the cell grow and divide. And You need your cells to multiply for you to grow, heal after an injury, or just create new healthy cells to replace dead ones, like dead skin. Unfortunately, when KRAS gets a mutation like G12C, the protein doesn’t listen to its supervisors anymore.

Almost as soon as it switches into its inactive state, it flips back into its active state, which results in a near-constant message for the cell to grow. And that uncontrolled cell growth is cancer. Equipped with all of that basic research, scientists could move on to the next phase: applied research.

There’s a clear goal: this mutated K-Ras protein is causing cancer, so they wanted to find a way to stop it. In this case, they wanted to force the mutant G12C K-Ras protein to stay in its inactive state by blocking it with a specially designed molecule, kind of like jamming something into the gears of a machine to make it stop. Researchers have a few factors in mind while searching for the best drug to do the job.

For one thing, any drug molecule would need to be as specific as possible to the mutant, always-active version of the K-Ras protein. You don’t want to accidentally jam the healthy Ras proteins and turn off cell division altogether. And there was another challenge: The G12C K-Ras protein is super, super smooth.

So smooth that it seemed like there was nowhere for a drug molecule to latch on at all, and therefore no way for it to slam on the brakes. This protein’s shape presented such a challenge that scientists started to call K-Ras “undruggable,” and research and development stalled for decades. Stalled, but did not stop.

In 2013, 30 years after the discovery of G12C K-Ras proteins, researchers at the University of California, San Francisco, found molecules that could slip into a small groove on the surface of mutant K-Ras proteins that’s only visible when the protein is in its inactive form. One molecule in particular, called Compound 12, holds really tightly to that small groove, stopping cells from growing and instead causing cells to die. This works because the molecule uses the twelfth amino acid in the mutant protein, which is a cysteine, to attach to the protein and make it inactive.

And because the healthy K-Ras protein has a glycine in that spot, it should not be affected by the drug. This discovery was great news. But while finding this groove could be considered the end of the applied research phase it is not the end of the story.

Next was the experimental development phase, and Compound 12 was just the starting point. The goal of this phase was, and is, to find a drug that can both stop the mutant protein from causing cancer and leave cells with healthy proteins alone. So researchers took that molecule, studied its shape, and iterated on it.

That means they tweaked it bit by bit and tested their new versions against both cells with mutated G12C K-Ras proteins and healthy cells, all in petri dishes, to find the most specific and effective tool. First, researchers at a company called Wellspring Biosciences took a closer look at Compound 12. They found that, even though Compound 12 sticks to the groove in the mutant protein, it doesn’t substantially affect cells containing them even after six hours of treatment.

So the researchers made changes to Compound 12’s individual parts. kind of like swapping out parts of a multi-tool, but instead of a screwdriver or a tiny pair of scissors, each subunit is a collection of atoms. By changing around several of those submolecular parts and measuring how they interacted with the mutant protein’s groove, they came up with a molecule that could lock the mutated protein into the inactive state and stop it from telling the cell to grow. They dubbed their new molecule “ARS-853.” Just because ARS-853 is good at turning off mutant K-Ras doesn’t mean it’s the best cancer treatment, though.

Even though it bound to the protein, it was not potent enough to actually be effective when they tested it in mice. So the same research team iterated on their molecule again, trying to make a new version that is more specific to the mutated K-Ras protein and more effective at lower doses. This time, instead of altering the molecular subunits around the edges of Compound 12, the team looked more closely at the subunits in the middle, called the scaffold.

They made a bunch of versions of the molecule and introduced it to cells with mutant K-Ras proteins. And after analyzing the new versions, they found they could improve Compound 12 by swapping out part of its scaffold for a quinazoline core. Quinazoline cores are a part of several cancer-fighting drugs approved in the U.

S. before 2017, so it made sense to try swapping it in. It turned out that ARS-853, the previous molecule they’d ruled out, had an unusual core that was so specific that it was difficult to improve the molecule more. So by switching it to a quinazoline core, these newer molecules had more room to improve.

And out of several quinazoline-containing varieties of the molecule, a version they called ARS-1620 came out on top. This version not only attached to the cysteine at position 12 but also attached to another amino acid, histidine, that’s also in the groove. Specifically, an atom on the quinazoline core is reaching out and holding onto the histidine, which shows just how important that core is to the drug doing its job.

That extra bond means that the drug molecule stays attached to the mutant protein in a more rigid, stubborn way. The researchers tested ARS-1620 in spherical cell cultures hat mimic the structure of a tumor. The molecule stopped cells with G12C KRAS mutations, while those without the mutation weren’t affected.

Then they tested the drug in mice with G12C K-Ras cancers, compared to mice with other cancers, and found it slowed the growth of tumors in the first group. Their paper, published in 2018, was the first to describe a molecule that could not only specifically block mutant K-Ras proteins from causing trouble, but also be taken orally by real, living animals and shrink tumors without causing serious side effects. After this, two other biotechnology companies, Amgen Research and Mirati Therapeutics Inc. picked up where Wellspring Biosciences left off.

Amgen researchers created a collection of new molecules based on ARS-1620, and then used advanced X-ray crystallography to see how their molecules interacted with G12C K-Ras proteins. And they found that when they added a new aromatic ring, which is this hexagon, to the quinazoline core, the molecule could wedge itself into another groove on the G12C K-Ras protein, right next to the histidine. That new aromatic ring made Amgen’s molecule about ten times better at holding onto the mutated K-Ras protein and keeping it inactive.

They named this molecule AMG 510. AMG 510 was able to stop growth and start tumor regression in mice with human tumor grafts with a lower dose than the Wellspring Biosciences molecule. Mirati Therapeutics’ molecule, MRTX849, also binds to the mutant cysteine, plus a few other amino acids: A glycine at position 10 on the mutant protein, and a glutamic acid at position 62.

By 2020, all three companies showed that their drug candidates could shrink tumors in mice by targeting the groove on G12C K-Ras proteins. Mirati and Amgen started testing their drug candidates in humans, marking the end of experimental development and the beginning of clinical trials. Clinical trials are necessary because there are a lot of differences between humans and mice — enough differences that drugs that work well in mice might not work at all, or even cause problems, when given to humans.

When Amgen tested their drug in four people with lung cancer, two of them had their tumors shrink. After six weeks of treatment, one participant who was assigned a lower dose of AMG 510 had their tumor shrink by 34 percent, and one with a higher dose had their tumor shrink by 67 percent. About half of patients treated in early trials with Amgen or Mirati Therapeutics’ drugs also saw their tumors shrink.

In January of 2021, Amgen announced they had enrolled 126 patients in another trial, and over a third responded to the treatment with an average tumor regression of 60 percent. And in May of 2021, ARS-510 was approved under the name sotorasib by the U. S.

FDA for people with non-small cell lung cancer with a KRAS mutation who didn’t respond to first-line treatments like chemotherapy and immunotherapy. Which is honestly amazing news. It has been 40 years since the G12C mutation in KRAS was linked to cancer, and 9 years since the breakthrough discovery of a small groove on the surface of an otherwise super-smooth protein.

But it goes to show that no matter how long it takes, thorough R&D is vital to making effective and safe new medications. And as more, different drugs are designed to target this kind of cancer, people will have more options to find the medication that works best for them. So, the science continues.

Thanks for watching this episode of SciShow! And thank you to today’s sponsor, Magic Spoon. They have best-selling cereal flavors full of childhood nostalgia, like Cocoa, Fruity, Frosted, and Peanut Butter.

But you know what it’s not full of? Sugar. Magic spoon has 0 grams of sugar, 14 grams of protein, and only 4 net grams of carbs in each serving; it’s also only 140 calories.

So it’s super tasty and great for different dietary needs, like if you’re gluten-free. If you want to bring out your inner child and grab a variety pack, click the link below or go to magicspoon.com/SciShow. You can use the promo code [SciShow] at checkout to get $5 off any order.

Plus, your order is backed with a 100% happiness guarantee, so if you don’t like it for any reason, they'll refund your money, no questions asked. Thanks again for watching! [♪ OUTRO]