Zack Hauseman

Protein-Protein Interactions | Structural and Chemical Biology

[Tito Adhikary @TitoA45]

Pleased to share the findings of my PhD thesis work now published in @CellReports

We found that MCL-1 regulates DNA integrity and cell-cycle progression independent of its canonical role of apoptosis blockade. MCL-1 is a high priority drug target for cancer, yet a series of clinical trials testing selective small molecule inhibitors of MCL-1 have been halted due to unanticipated toxic side effects. Indeed, in 2019, Amgen halted the Phase 1 clinical trial of two of its lead MCL-1 inhibitors due to fatalities associated with cardiotoxicity. These adverse clinical outcomes raise the possibility that side effects from targeting MCL-1 could derive from its canonical and noncanonical roles. 

13 years ago in a landmark study, Beroukhim and colleagues surveyed 3000+ copy-number number profiles from multiple cancer types found that MCL-1 was one of the Top 10 most commonly amplified genes across human cancers. In the Walensky Lab, we have long been fascinated about this protein. Among the 6 known anti-apoptotic proteins, MCL-1 stands out due to several distinctive features, including being the only BCL-2 family anti-apoptotic whose deletion has been found to be embryonically lethal. Additionally, MCL-1 has been found to regulate a host of other critical physiologic functions - majority of which cannot be rescued by reconstituting one of its anti-apoptotic homologs. We were therefore intrigued by a key question: What makes MCL-1 the preferred anti-apoptotic member and explains its oncogenic supremacy over its homologs?

When we surveyed the cancer cell susceptibility profile of S63845, a highly specific MCL-1 inhibitor across 1000+ cancer cell lines, we remarkably found that the pharmacologic profile of MCL-1 better matches that of anti-proliferative than pro-apoptotic drugs, in stark contrast to BCL-2 or BCL-XL inhibitors which largely cluster with other pro-apoptotic agents. This discovery not only opens the door to expanding the applications of MCL-1 inhibitors, both as single agents and in specific combinations beyond the current indication of MCL-1 dependent cancers, but also reveals novel mechanism-based therapeutic window concerns that warrant serious caution. As an example, we demonstrate that the combination of vincristine and S63845 lead to significant loss in body-weight in mice over single agent treatment arms.

Rigorous investigation into MCL-1 biology has been confounded by its multiple isoforms, structural domains of unknown structure and function, and the challenges in distinguishing noncanonical activities from the apoptotic response. We took these challenges very seriously and used a large battery of novel cell line systems, including in vivo analyses, and a breadth of orthogonal omics approaches all with rigorous genetic controls and discovered that MCL-1 regulates the very fidelity of DNA and progression through the cell cycle – functionalities that we prove are wholly independent from the established role of MCL-1 in suppressing mitochondrial apoptosis. Importantly, and unexpectedly, we find that both genetic deletion and small-molecule inhibition of MCL-1 block proliferation in cultured cells, which coincides with DNA damage.

Finally, by performing affinity enriched mass spectrometry (AE-MS) across each stage of the cell cycle with the @GygiLab, we discover for the first time several new protein complexes engaged by MCL-1, including the MCM protein complex that links MCL-1 to the regulation of DNA integrity and cell cycle progression. The MCM complex is essential in all cells and is the very protein complex that unwinds double-stranded DNA at replication origins in the S phase. Even more intriguingly, using a cool PLA experiment with the @ChowdhuryLab we discover that the MCL-1:MCM complex interaction is highly situational, occurring only upon induction of replicative stress -  suggesting that MCL-1 assumes a protective role in maintaining DNA integrity in cells.

https://t.co/zTGMHCNd2N

[Mark Tye @Mark_A_Tye]

@mazit @NatureComms Very excited to see my manuscript published in @NatureComms about our #medicinalchemistry efforts to develop inhibitors of ProRS for #malaria. This work is supported by the development of a single step, homogeneous TR-FRET assay. Truly grateful to @Mazit and all our coauthors

[Zack Hauseman @ZHauseman]

There are many people and support structures for me to thank, including a great team and environment at Novartis. I had excellent mentors throughout and would recommend coming here for a postdoc any day! And to my friends, family, and wife, tons of gratitude. 5/5

[Zack Hauseman @ZHauseman]

I’m excited to share that my (official and formatted!) paper has been published in @Nature. The manuscript is centered around a high-resolution structure of a key protein complex for activation of the MAPK pathway- the MRAS-SHOC2-PP1C holophosphatase.

https://t.co/wgGDhHi1DR

[Zack Hauseman @ZHauseman]

These findings provide a much better understanding of this node of MAPK activation. Will be absolutely fascinating to see where the field takes this next. The relevant links:

https://t.co/46LqCSoBqV

https://t.co/8HWmXNtNcl

https://t.co/LvDHEBI6cE

4/

[Zack Hauseman @ZHauseman]

My final question, to which I naively don't know the answer, is how much industry scientists are considered. While they might be even less amenable to the current setup (unpaid), there is unbelievable expertise there. Is there a way to include them? 3/3

[Zack Hauseman @ZHauseman]

This is true, but I think a really important discussion -reviewer pay- is missing. Some good points about giving reviewers more credit in meaningful ways, which is great. But ultimately expecting critical labor for free is part of the problem. 1/

[Amanda Murdie @AmandaMurdie]

1/ Peer review is in trouble! So much of the knowledge we produce & share rests on the idea that our work goes through a rigorous review by experts. After serving as an editor-in-chief for 5 yrs. & an associate editor for 3 yrs., I'm worried that our system is in trouble:

[Zack Hauseman @ZHauseman]

I also think reviews as a prerequisite to submit would disproportionally harm early stage scientists. Having journals blocked to those who haven't even been invited 3x would hurt free publishing. I agree we should find ways to encourage and reward quality reviews in general. 2/

[Zack Hauseman @ZHauseman]

What an amazing opportunity to be able to spearhead this project! Really enabled by the collaborative NIBR environment, a unique framework from the innovation postdoc fellowship, and top notch scientific mentorship.

[Jay Bradner, M.D. @jaybradner]

SHOC2 at atomic resolution via NIBR in @Nature. Gorgeous structure and mechanistic insights on RAF activation, cell proliferation. A foundational contribution to the scientific understanding of RAS biology in human cancer. https://t.co/2AHgDZsOeR

[Journal of Emerging Investigators @JEInvestigators]

Get your JEI shirt! Various colors with the JEI logo. Short sleeves ($25), long sleeves ($30). 25% of the price goes back to JEI. They won't last forever.

[Zack Hauseman @ZHauseman]

@PhDVoice @PostdocVoice Acceptable if the peer-reviewed version won't be out before a publication deadline, and you have a clear/critical reason to cite (i.e unique content relevant to your own discussion/findings). Otherwise it's important to only cite peer reviewed work.

[Ethan Mollick @emollick]

The public colleges of New York, Texas, and California are great engines of social mobility in America. They move many born in the lower 20% of income to the top 20%

Our most elite universities move smaller numbers from the bottom 20% income to the top 1% https://t.co/DhjtaUv48s

[Manfred Jung @ChemEpi]

#medchemtwitter : What are biggest success stories w. approved small molecule drugs in the last 10 or so years? Not in sales but therapeutic breakthrough, maybe even measure of success (money saved or Qualys)? Or personal favourites? Any thoughts e.g. @HartungIngo @g_sbardella