ASH 2017: Dr. Richard Furman on the importance of MCL-1 in CLL (chronic lymphocytic leukemia)

[hsouter]

Just watched a video on MCL-1 and thought our group might be interested (if not already aware!).

From the CLL Society website:

As good as venetoclax is as a single agent, there are now many studies that show even more remarkable responses occur when it is used in combination with ibrutinib or rituximab. See this on the Murano trial from ASH 2017 that combined V+ rituximab. We soon will share the V+I data from ASCO 2018.

An MCL-1 inhibitor combo with V, if safe and tolerable, might seal the deal in CLL. Only time and trials will tell.

Here is my interview with my friend and CLL Society Medical Advisory board member, Dr. Rick Furman from ASH 2017

Watch this short video in plain language about MCL-1.

youtu.be/rdAczMjt_A0(Not working as expected?)

[BettinaB]

I was just going to post this link - sounds really interesting, and MCL 1 is not an acronym I've heard before. Does anyone know more?

[Cllcanada Top Poster CURE Hero in reply to BettinaB]

Here is a general paper on MCL-1... Myeloid cell leukemia 1, part of the BCL2 family that Venclexta (venetoclax) works on...

ncbi.nlm.nih.gov/pmc/articl...

In CLL and there are a few experimental MCL-1 inhibitors in development, I believe SYK works on the same family of proteins...

~chris

[BettinaB in reply to Cllcanada]

Thank you Chris! You never cease to amaze me.

[Cllcanada Top Poster CURE Hero in reply to BettinaB]

Certainly welcome... here is everything you never wanted to know about MCL1

ncbi.nlm.nih.gov/gene/4170

[BettinaB in reply to Cllcanada]

Ouf. Vast is the ocean of things I don't know, and don't even begin to understand...

But what a miracle is life on this planet.

Thanks Chris!

[Wroxham in reply to Cllcanada]

Thanks Chris. Can't even begin to digest this at the moment, but I have downloaded it for future reading.

What I did like to read was that they are expanding the "clax" family. Also

Of the many combinations that are going to be looked at in the future.

Sue

[gardening-girl in reply to Cllcanada]

Chris, the paper you provide the link to (ncbi.nlm.nih.gov/pmc/articl...

)

provides an excellent example of the trials and tribulations of searching for an effective small molecule inhibitor for MCL-1. The figures at the end of the paper (past the references) show just how the small molecules must bind to a specific groove in the MCL-1 protein in order to block its antiapoptotic activity.

Again, thanks for your links.

[Cllcanada Top Poster CURE Hero in reply to gardening-girl]

Groovy...😆

[gardening-girl in reply to Cllcanada]

All I can say is that you are always in the groove, Chris!

[Wroxham]

Thanks for this h Souter.

Sue

[gardening-girl]

Heather and Chris, the links that you provided relative to MCL-1 are wonderful, and have led me to spend more time reading about MCL-1 and ways to target it. I am particularly interested since I’m 17p deleted, now on ibrutinib, and anticipating treatment at some point with venetoclax. I was interested to learn that in folks who fail venetoclax treatment a common reason can be due to elevated levels of MCL-1. In addition to the small molecules targeting MCL-1 highlighted in your post Chris, I see that cdk4/6 kinase which is required for MCL-1 function is being targeted in an open Phase 1 trial testing the safety of the cdk4/6 inhibitor Voruciclib/P1446A-05. clinicaltrials.gov/ct2/show.... The trial is open for CLL as well as DLBCL.

Thanks for the links!