'Undruggable' cancer-causing protein meets its match

[NNadir]

This showed up in my Nature Briefing this morning:

‘Undruggable’ cancer-causing protein meets its match

Subtitle:

Researchers have found a compound that can block a mutant protein linked to many tumours.

The article is brief:

A promising molecule could lay the foundations for a way to treat some of the deadliest cancers1.

About one-quarter of all cancers carry mutations in a protein called KRAS, which helps to regulate cell growth. Researchers have struggled for decades to design therapies that inhibit the protein. One drug that targets a mutant form of KRAS has recently reached the market, but this therapy does not work against KRAS with a mutation named G12D (KRASG12D). This version of the protein, the most common KRAS mutant, is found in many pancreatic and colorectal tumours.

Jill Hallin at Mirati Therapeutics in San Diego, California, and her colleagues studied a molecule called MRTX1133 that can block the activity of KRASG12D. They found that MRTX1133 binds to the mutant 700 times more readily than to normal KRAS, and that the compound kills laboratory-grown cells that make KRASG12D...

The original article is here:

Hallin, J., Bowcut, V., Calinisan, A. et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. Nat Med 28, 2171–2182 (2022).

This is not the KRAS mutation with which I've heard about, a mutant at the same residue, G12C where glycine is substituted by cysteine at the 12th residue of the protein. A drug for this target is marketed, and it has some efficacy in some cancers. G12D is substituted by aspartic acid at the 12th residue of the protein.

The structure of MRTX1133 is given in the full paper:



It is said to bind only to G12D mutants, and not the normal KRAS protein. The binding site is shown as well in the full paper:



The cancers it may treat, should it pass through clinical trials and show few dangerous AE (Adverse Events) include some very intractable cancers, notably pancreatic cancer.

Cool.

[Laffy Kat]

1. The chemistry was too basic science for me to understand.

Yet, this is great news. Another victory for medicine.

[I_UndergroundPanther]

2. Awesome

And very very cool!

[SharonAnn]

3. My husband died 10 years ago from a colon cancer with this "undruggable" KRAS gene

We knew from the outset that then current treatments weren't that effective. But he fought it until the bitter end.

I'm so glad to hear that this kind of progress has been made and that it may help cure other people.

[flamingdem]

4. A family member died of KRAS

It was brutal. Nothing worked

[littlemissmartypants]

5. ❤️

[eppur_se_muova]

6. Yeah, I would've guessed the structure was something like that ...

... NOT!

Interesting -- three fluorine atoms, and each one must be necessary or they wouldn't have included them. The guys who design these drugs are getting better in leaps and bounds. They're certainly working in larger groups -- 30 coauthors on this article ! I'd be interested to know how much in silico modelling preceded this success, but, given that it's part of an ongoing effort across the field, I doubt that could be accurately guessed.

The intro to the article offers the possibility of further fine-tuning, so maybe lots more to come.