Matthews Group

@pennchemistry.bsky.social, @pennmedicine.bsky.social, @biorxivpreprint.bsky.social, @who.int, @covalentmod.bsky.social

14/14 We are extremely excited to leverage these new findings for (pre)eclampsia and glioblastoma drug development, and we are actively seeking investors and partners for our company, Zenagem, LLC, to move forward.

13/14 suggests that the organohydrazine might be modified and repurposed for the treatment of glioblastoma. Indeed, we found that just a single exposure to HYZ causes GBM cells to senesce.

12/14 Despite widespread recognition of its high potential value as a drug target, no specific inhibitors of ADO have been reported. The demonstration that HYZ inactivates ADO thus fills a second need and

11/14 An amazing bit of serendipity is that ADO has emerged as a target for treatment of the recalcitrant brain cancer, glioblastoma (GBM), which has an average survival time of < 18 months. This disease also touched my life: my maternal grandfather died from it before I was born

10/14 Kyosuke’s in-cell and in-vivo proteomics experiments shows that the drug subsequently alkylates one of the enzyme's His ligands, irreversibly inactivating it. This specific binding and mechanism-based inactivation explain the drug's high selectivity for ADO.

9/14 regulators of G-protein mediating signaling systems that control vascular tension, thus connecting HYZ's target to its effects. Our crystal structure with collaborator Aimin Liu at UT San Antonio shows that HYZ chelates the mononuclear metal cofactor of ADO.

8/14 more importantly, cysteine at the N-termini of certain proteins to initiate their proteosomal degradation via the Cys/N-degron pathway. Its substrates include RGSs (a.k.a. GAPs),

7/14 In our new study led by Kyosuke Shishikura, we provide evidence that the target is the enzyme 2-aminothiol dioxygenase (ADO). ADO oxidizes the sulfur atoms of free cysteamine and,

6/14 But for preeclampsia, it remains a therapy of choice, securing its place on the World Health Organization’s List of Essential Medicines.

Despite the drug's seven decades’ history, its target has remained unknown.

5/14 Hydralazine (HYZ) is an organohydrazine drug that was introduced into the clinic more than 70 years ago as a vasodilatory antihypertensive. For most types of high blood pressure, it has been supplanted by newer drugs.

4/14 In my generation, my sister was treated for preeclampsia and delivered prematurely. I also had a premature labor, and complications from the emergency caesarian section nearly added me to the grim preeclampsia statistics.

3/14 My maternal grandmother fell into a coma in her second trimester, and my paternal grandfather’s first wife died suddenly of cerebral hemorrhage two hours after giving birth to my Dad’s half-sister.

2/14 Preeclampsia is a pregnancy-induced hypertension that affects 5-15% of women. It is a leading cause of maternal and neonatal death worldwide, and its incidence is on the rise. Growing evidence suggests a genetic link. My family appears to have the genetic susceptibility.

1/14 Our latest study just out on BioRxiv [https://www.biorxiv.org/content/10.1101/2024.12.19.629450] has unusual personal significance for me. It connects two apparently unrelated diseases – (pre)eclampsia and glioblastoma – that have both impacted my family.