Tito Adhikary

Biotech Venture Capital | Associate at Eos BioInnovation

[Loren Walensky @LorenWalensky]

Congratulations to Sophia Tang and the entire collaborative team from the Walensky and Segal labs on the publication of a new strategy to tackle chemotherapy-induced peripheral neuropathy by targeting the IP3 receptor with a BCL-w BH4 mimetic @CellChemBiol https://t.co/iRavGOX6hw

[BowTiedBiotech 🧪🔬🧬 @BowTiedBiotech]

Peptide innovation is coming. Good investors are always a step ahead.

De novo development of small cyclic peptides that are orally bioavailable

🫵🤣Skeptical chemists we see you!

https://t.co/LbOyA1PFn6

[Tito Adhikary @TitoA45]

Great work from my colleague Matt McHenry reporting on a covalent inhibitor for the death executioner protein BAX.

[Loren Walensky @LorenWalensky]

Congratulations to Matt McHenry & the entire team, including collaborators @realJimWells @GygiLab @jrengen @tmonsterphd, on the discovery of a covalent inhibitor of BAX, a blueprint for developing drugs to protect cells from unwanted cell death. https://t.co/3a0xXzpN6a

[Loren Walensky @LorenWalensky]

Congrats to 1st-author Greg Bird and the whole team on advancing our stapled lipopeptide platform to combat highly pathogenic viruses of pandemic potential. We need more on-demand agents that prevent infection & arrest transmission. @DanaFarber @neidl https://t.co/AAsuaaWGv7

[Tito Adhikary @TitoA45]

@MrJeffKarp Congrats Jeff! Pre-ordered a copy

[Tito Adhikary @TitoA45]

@FadiNajm @JD_Buenrostro @broadinstitute @GRO_Broad Congrats man, well deserved!

[Tito Adhikary @TitoA45]

@SahilBloom Ah no way, all the more reason then!

[Tito Adhikary @TitoA45]

@FadiNajm Congrats buddy!

[Tito Adhikary @TitoA45]

A big thank you to all my co-authors, and my mentor @LorenWalensky without whom I wouldn’t be here. Special thanks to my collaborators especially Joao Paulo from the Gygi Lab, @ShrabastiRoych1 from the Chowdhury Lab, and Joe Opferman from St. Jude. Thank you also to my thesis advisors Roz Segal, David Pellman and Tim Mitchison for years of invaluable feedback and advice.

[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

[Tito Adhikary @TitoA45]

@theserbianator @LorenWalensky @CellReports @theNCI @DanaFarber @BBS_Harvard Thanks Aleks hope all is well!

[Tito Adhikary @TitoA45]

@LorenWalensky @CellReports @theNCI @DanaFarber @BBS_Harvard Thanks Loren! :)

[Tito Adhikary @TitoA45]

Thanks to @ForesiteCapital, @GVteam, @JNJInnovation, Longitude Capital, @MissionBioCap, Omega Funds, @SalesforceVC, Sofinnova Investments, and @WilmerHale for the scholarship support, and @VCForward and @NVCA and Berkeley Law for the unique opportunity!

[Tito Adhikary @TitoA45]

Grateful to be awarded a full scholarship by @VCForward for Cohort 14 of #VCUniversity!

Super excited to dive into the fundamentals of VC, learn from VC mentors, and build new relationships alongside like-minded peers from diverse backgrounds across the country

[Venture Forward @VCForward]

Cohort 14 of #VCUniversity starts today! 🎉 We’re proud to recognize the 40 new and aspiring VCs who were awarded our full scholarships to join the program. Get to know these up-and-coming investors. 👉

[Sahil Bloom @SahilBloom]

Important Rule for Life: Never bet against the person who just keeps showing up.

[Tito Adhikary @TitoA45]

@SahilBloom Congrats Sahil!

[Tito Adhikary @TitoA45]

@BowTiedBiotech Very possible!

[Tito Adhikary @TitoA45]

@theserbianator Happy bday man!

[BowTiedBiotech 🧪🔬🧬 @BowTiedBiotech]

#biotech old timers should not ignore this trend….be open to new models. Times are always changing adapt or become extinct.

https://t.co/KLp5kZNZww