GBT-601 (HbS polymerization inhibitor) ✔️
Pfizer/Global Blood Therapeutics
Confirmed correct on December 16, 2023 according to NCATS GSRS.
GBT-601 (aka GBT021601) is an oral hemoglobin S (HbS) polymerization inhibitor developed by Global Blood Therapeutics, a subsidiary of Pfizer (PFE 0.00%↑), that is currently in phase 2/3 trials (NCT05632354, NCT05431088) for the treatment of sickle cell disease (SCD). It is a 2nd generation HbS polymerization inhibitor that is supposed to be an improvement (lower dose, better PK) over the first-in-class compound, Oxbryta (voxelotor), which was FDA-approved for SCD in November 2019.
Sometimes the path to compound ID is straightforward. Other times it is meanders and is circuitous. For this GBT-601, it was the latter (oof).
Some brief biology context
A refresher the on the role of HbS in SCD and how an HbS polymerization inhibitor can help in this context: there are 3 “normal” forms of hemoglobin in humans
HbA: major isoform in adults. Consists of 2 alpha and 2 beta chains
HbA2: minor isoform in adults. Consists of 2 alpha and 2 delta chains.
HbF: predominant isoform in fetuses
HbA is a tetramer, comprised of 2 alpha chains and 2 beta chains. However, in folks with SCD, at least 1 of the beta chains has an E6V single nucleotide polymorphism (SNP). This mutated form of HbA is called HbS. When both beta chains of HbA have an E6V SNP, this results in sickle cell anemia.
Under normoxic conditions, the E6V SNP does not alter quaternary structure: that is to say, HbS ≈ HbA. But under low O2 conditions, when HbS is in the deoxygenated state, HbS polymerizes and forms fibrous precipitates that can lead to hypoxemia, ischemia, pain, necrosis, etc.
This is where HbS polymerization inhibitors come in: GBT-601 (and voxelotor) stabilize the oxygenated state of HbS to mitigate being in the deoxygenated state that lead to bad things (see above).
Patently obvious!
We now have the biology framework. Another later-stage clinical compound without a publicly disclosed structure! Right up my alley.
I began my search by jumping to the patent landscape. Here, I found 5 patents from GBT on HbS polymerization inhibitors. 4 composition of matter (COM) patents and 1 solid forms patent:
Solid forms of a modulator of hemoglobin (WO2022241278A1)
Methods of making a modulator of hemoglobin (WO2022241286A1)
Modulators of hemoglobin (WO2021202284A1)
2-Formyl-3-hydroxyphenyloxymethyl compounds capable of modulating hemoglobin (WO2020106642A8)
Modulators of hemoglobin for the treatment of sickle cell disease (WO2020072377A1)
I mentioned in previous posts that a solid forms patent is a huge tip in the right direction. The solid forms patent provides a structure (Compound 1) and preparation method, but no biological data.
Nonetheless, it is a good starting point. Even without biological data, the international search report (ISR) at the very end points to previous patents where the compound of interest has been described.
Take nothing for granted
The ISR points me to example 7 in WO2020106642A8, “2-Formyl-3-hydroxyphenyloxymethyl compounds capable of modulating hemoglobin,” a COM patent.
However!
When I look, I see that example 7 is NOT the same compound as the one described in the solid forms patent. Spot the difference?
That’s right: the solid forms patent on the left (‘278) has a pyridinyl moiety but the COM patent on the right (‘642) has a pyrazinyl moiety. In actuality, the example in the ‘642 patent that aligns with Compound I in the solid forms patent is example 8.
Okay, now that I’ve zeroed in on the same compound in both patents, it’s time to see if Compound 1 (example 8) is actually GBT-601.
Here is where I begin grasping for straws (aka leads). Any biological data that I can find in these patents will be helpful as I try to match data across patents, company presentations, etc. From the ‘642 COM patent, I now know the following things about Compound 1:
When Hb is incubated at a 1:1 molar ratio with Compound 1, there is a 79.8% change in p50 (partial pressure of O2 at which Hb is saturated with O2).
Does not induce hCYPs at 30 µM
In S-D rats at 10 mg/kg PO, the t1/2 is 69 hours and the blood/plasma ratio is 105.
Honestly, not that much to go off of here. No memorable graphs, only tables. Not super helpful, from a detective point of view. But alas, this is what we’re working with.
And just to be sure that I or the ISR folks are not missing anything (they’ve already let me down once!), I checked the other COM patents to make sure nothing on Compound 1 is in there. Variations on the pharmacophore but nothing on Compound 1.
Databased
With the patent data in mind, I now attempt to scour the internet for matching clues. One of my favorite databases to do this is the Global Substance Registration System (GSRS), which is a database containing registered active pharmaceutical ingredients (APIs) under clinical investigation.
Not all APIs under clinical evaluation are listed in the GSRS (example: TAK-994 is not). But sometimes, you can get lucky. And I was feeling lucky.
So I simply searched “GBT-601”. Lo and behold, we got something!
The GSRS had been my go-to for the previous 5 compounds that I’ve covered. But I had always come back empty-handed. So I had become conditioned to skip the GSRS on my first-pass.
But this GBT-601 hunt has reminded me that I should go back to looking here first again!
Codes and Keys
In the GSRS, there are 2 subsections that list the codes associated with the compound. As it turns out, GBT-601 has been granted FDA Orphan Drug status.
Clicking on the “877122” hyperlink returns the FDA database for orphan drug designations & approvals. Helpfully, this provides the IUPAC name for GBT-601 (!!!), which is (S)-2-hydroxy-6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin- 3-yl)methoxy)benzaldehyde.
Easy. Enter the IUPAC name into ChemDraw “Name to structure” returns the structure (featured above).
As a check, I also plug and chug the record UNII code “UK749B4S16” into PubChem and search as text (not molecular formula!).
And there you have it: GBT-601! Same structure as Compound 1 in the solid forms patent (‘278). Turns out, I could’ve just checked “GBT-601” in PubChem first (ahhh).
Honestly, a little underwhelming, since the patent search had little to do with deciphering the final compound. But this was a good reminder to check my assumptions about checking the GSRS and PubChem first, even if they have failed me for previous compounds.
That’s it for now. Catch y’all next week :)
P.S. — A note of appreciation :)
Thank you everyone who has subscribed to Molecular Sherlock! From med chemists in academia & industry, to folks in venture capital, finance, and beyond, these pages have drawn science-minded people across sectors. I am amazed by the appetite for this sort of content and will continue to do my very best to unearth interesting molecules for you all! Please know that you all have my ears and that they are open to any suggestions you may have!
Thank you especially to my paid subscribers <3 Sometimes these compounds can take a many, many, many hours to figure out, so your support really means a lot to me. Beginning next week, as special thanks, paid subscribers will receive early access (1 week advance) to posts, in addition to having access to downloadable slides & archive.
If you like this work, please do share these pages with your friends!
-vcy
Have a compound that you want me look into? Suggest a compound here.
