Thread by @cenmag

Hello everybody, @LeighJKBoerner here, C&EN organic and medicinal chemistry reporter. I’ll be live tweeting the First Disclosures of Clinical Candidates from the #ACSSpring2022 MEDI division. This year it goes from 11 to 12:50 pm et, and then again from 1 to 2:55 pm.

If you think I'll be tweeting cute molecules again this year, you are very right.

Session presider Nicole Goodwin from @GSK
has her introduction. Let's do this

She comments on the persistence and determination of the scientists on working through the COVID-19 pandemic #ACSSpring2022

Nikki Goodwin is thanking Goodwin Procter for the sponsorship. No relation on her part #ACSSpring2022

FYI, I'm watching virtually, and my sound on the talk is kind of going in and out. So pls forgive if I miss anything #ACSSpring2022

First presenter is Dustin Mergott from Eli Lilly, who's presenting an enzyme inhibitor to treat Alzheimer’s and other neurodegenerative diseases #ACSSpring2022

Title of his talk is "Discovery and early clinical development of LY3372689, an O-GlcNAcase (OGA) enzyme inhibitor" #ACSSpring2022

In Alzheimer’s Disease the protein tau accumulates in the brain. OGA slows tau. #ACSSpring2022

OGA and OGT puts a sugar on and off the tau protein. If block OGA, may slow aggregation of tau. #ACSSpring2022

Used a mouse model early on to see if they can slow down the aggregation of tau. Can reduce aggregation of tau by 50% by using OGA inhibitors. But these studies are really difficult to run. #ACSSpring2022

OGA is a glycoside hydrolase, and it's mechanism is substrate assisted. Wanted to develop inhibitors competitive of this process. #ACSSpring2022

Did screening studies, found 2 compounds that were efficient at preventing aggregation, wanted to follow up on these #ACSSpring2022

Got xtal structures of both compounds bound to OGA in a pocket. One engaged OGA better than the other #ACSSpring2022

Got good results with 3 compounds, but only one got through CNS well #ACSSpring2022

More potent compounds were more lipophilic #ACSSpring2022

Added F atom in more promising compounds, was able to bind OGA better. #ACSSpring2022

Wanted to use enzyme occupancy to drive optimization. But had short half lives for this occupancy. But one compound that couldn't get into the CNS well had a good half life for enzyme occupancy, even at low doses. #ACSSpring2022

Just showing occupancy of OGA isn't enough to drug target though #ACSSpring2022

after 48 hours, shows a less potent concentration response due to upregulation #ACSSpring2022

Studied enzyme binding kinetics, q big variation in T 1/2, from 16 minutes to 5-20 days. What does this mean for enzyme occupancy? #ACSSpring2022

Studied 4 compounds after acute and 10 day dosing, compound 9 showed potential loss of potency, but compound 11 suggested no impact on upregulation #ACSSpring2022

But why these differences? Looked at xtal structures, compound 9 vs 11. For 11 when bound, showed closed confirmation for protein, maybe that's why it has a slow off-rate behavior, but it's more complicated than that #dang #ACSSpring2022

One compound had good human performance, put into non-clinical safety studies, but it failed. #ACSSpring2022

So went back to another compound, looked at single dose human studies #ACSSpring2022

Looked at ICH (International Conference on Harmonisation) guidance, tried to advance compound 5, found good safety, and so could test in humans. #ACSSpring2022

Found a nice dose dependent increase, half life was 6 hours. Also looked at a PET study, 5 mg dose hit targets after 24 h. Went with this for initial dose #ACSSpring2022

Single oral dose of 5 mg showed high occupancy of the enzyme at 2 h, then at 24 h. Dropped only a few % pts. #ACSSpring2022

Tried a 1 mg dose, still had good occupancy after 24 h. #ACSSpring2022

Then went on to fully characterize the compound in regard to the human PK-EO relationship. Went on to more studies then #ACSSpring2022

Tested 3 doses of this compound, only small adverse effects #ACSSpring2022

This compound was still in the OGA enzyme 14 days after dosing of 1 mg. Can safely advance to Phase II study #ACSSpring2022

Here's the compound, LY3372689 #ACSSpring2022

In Phase 2 study, have 330 participants, still enrolling, should be done in June 2024 #ACSSpring2022

Questions now! Why didn't you target OGT and only targeted OGA, would inducing expression of OGA have an effect? #ACSSpring2022

OGA is a more druggable target, Mergott said #ACSSpring2022

Missed that question, sorry! Next one: are there any concerns of the aminothiazole metabolite #ACSSpring2022

Less than 10 mg dose, low dose, shouldn't be a problem #ACSSpring2022

Q: other companies has reported some safety concern, any comments? Mergott said that they haven't seen the same problems in their studies #ACSSpring2022

Q: Given that you mentioned multiple compounds had failed in pre-clinical toxicology studies, can you comment on what gave you confidence that LY3372689 had the potential to be better tolerated in multiple dose studies? #ACSSpring2022

Performance of compound 6 was strong, was about 10x lower with compound 5, thought this was better for safety #ACSSpring2022

Q: baseline PET seems quite different? A: see some variability in baseline and saw some in other studies, ran a test retest study to look at bioavailability of tracer, falls within standard variability #ACSSpring2022

Next up: Jeffrey Johannes from AstraZeneca talking about a cancer drug #ACSSpring2022

Title of talk: Discovery and first structural disclosure of AZD9574, a CNS penetrant PARP1 selective inhibitor #ACSSpring2022

PARP family is small enzyme family, involved in DNA damage and repair. PARP1 and PARP2 are closely related. #ACSSpring2022

From the National Cancer Institute: "A substance that blocks an enzyme in cells called PARP. PARP helps repair DNA when it becomes damaged. DNA damage may be caused by many things, including exposure to UV light, radiation, certain anticancer drugs, or other substances...

... In cancer treatment, blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Also called poly (ADP-ribose) polymerase inhibitor."

PARP mechanism of action on DNA involves small molecules turning off PARP or trap it on the DNA

Results in a lot of double strand breaks in DNA, which it needs to repair before it divides. But in cancer cells, worse at repairing ds DNA breaks and can lead to cell death #ACSSpring2022

Looked at compounds that inhibit PARP1 and PARP2. Many compounds out there that do some part of this, looking at some of these as models #ACSSpring2022

Last year described AZD5305, but is excluded from CNS, so going forward using the good traits they want, but trying to make it get through to CNS better, among other things #ACSSpring2022

Started with AZD5305, looked at xtal structure to understand how it's binding, some areas are the same between PARP1 and PARP2 #ACSSpring2022

But difference is in how the PARPS bind waters, so how could they change the drug structure to take advantage of this? #ACSSpring2022

All carbon core gave the best results, including N in the main ring gave the best CNS penetration results tho #ACSSpring2022

Carboxamide was playing a role in CNS exclusion, taking it off gave better CNS penetration. But removing polarity made the compounds have secondary pharmacology, which they didn't want bc bad #ACSSpring2022

Found ortho trick to get better efflux and cell potency, looked at F compounds #ACSSpring2022

Found that there was a sweet spot for permeability #ACSSpring2022

Then went back to core of structure, when put NH next to F, had good selectivity and potency #ACSSpring2022

When F the core, clashes with backbone carbonyl. Also pi stacking of Tyrosine makes it more stable #ACSSpring2022

here’s the compound #ACSSpring2022

Glucuronide is major metabolite in humans #ACSSpring2022

AZD9574 has better activity in BRCAm cells #ACSSpring2022

Thinks they have a pretty good profile in the cells with AZD9574. The compound traps PARP1 to DNA but not PARP2 #ACSSpring2022

In vivo mouse model, AZD9574 showed a strong anti-tumor response in MDA-MB-436 cell line #ACSSpring2022

Need sustained engagement with the target to see regression in the tumor #ACSSpring2022

In a mouse brain model, AZD9574 also showed good efficacy, at 3 mg go 155 days, at 30 mg went 189 days without half the mice dying. #ACSSpring2022

Johannes is wrapping up here, says AZD9574 that will soon enter Phase 1 clinical trials #ACSSpring2022

Q: How do the dual pgp/bcrp efflux values compare to the sum of the discrete pgp and bcrp efflux values?

A: don't have a cell line to look at this #ACSSpring2022

Another in person question that I could quite hear, sorry ppl. The answer is something about CNS and efficacy, if that helps any at all #ACSSpring2022

Q: can you comment more regarding secondary pharmacology hits for non amide inhibitors? A: some adenosine inhibitors, can't remember all the targets #ACSSpring2022

Small break here before the next speaker. about 2 min #ACSSpring2022

We're getting some funky synth music in the virtual room here. Tune in to groove out #ACSSpring2022

Ok we're back! Next speaker is David Limburg
from Pfizer talking about the development of a drug to treat topical inflammatory skin conditions #ACSSpring2022

Title of talk: The Discovery of PF-07038124, a boron-containing Phosphodiesterase 4 inhibitor for the treatment of Inflammatory Diseases. #ACSSpring2022

Atopic dermatitis and psoriasis are chronic skin disorders, lots of ppl have them (including me, I have psoriasis and so do a lot of my family) #ACSSpring2022

Also Limburg used "plethora" in a sentence so he gets cool word points #ACSSpring2022

Can raise cycli AMP, which can activate protein kinase A and downregulate the inflammatory response #ACSSpring2022

that's 'cyclic'

EUCRISA is a topical drug in the past, which is a PDE4 inhibitor. was approved in 2016, can use in ppl as young as 3 months #ACSSpring2022

But there are antibody therapies too, so wanted to combine these with older drug to make a next generation topical drug. Used "topical by intent" approach #ACSSpring2022

Boron is cool! he says. It has a place in drug discovery, it's a strong LA and electrophile, can make stable bonds. Mostly trigonal planar, but can do a tetrahedral formation as well, good for biological nucleophiles #ACSSpring2022

There are B containing drugs out on the market, Bortezomib (2003), Tavaborole (2014), and Vaborbactam (2017) #ACSSpring2022

Design strategy! Wanted to build off what they knew with crisaborole, started with an unsaturated oxaborole ring #ACSSpring2022

Had an initial lead in hand, then considered saturating oxaborale ring, this incorporated a chiral center. Then looked at catechol substitution, changed CH3 to n-propyl. but taking them off entirely dropped the effectivity. Then replaced core with a N heterocycle #ACSSpring2022

Here comes the structure, hold please for drawing #ACSSpring2022

#ACSSpring2022

I missed a lot while I was drawing that, but he basically said that this compound was way hard to make #ACSSpring2022

They looked at asymmetric routes to scale this up, Cu catalyzed cross coupling was a no-go bc it needed too much Cu #ACSSpring2022

Were able to use lipozyme RM-IM for biocatalysis, but this way used a lot of steps #ACSSpring2022

They ended up going via an enantioselective hydroboration. Used Bpin and an Ir COD catalyst #ACSSpring2022

Tried using catechol borane instead of Bpin, this helped address the Bpin issue. Also switched from DCM to THF, which helped yields, thinks that the catalyst was more soluble in THF #ACSSpring2022

Still needed to deal with making a chiral compound, which can be a pain. Ended up using a ferrocene diphenylphosphine compound. Got 98% ee and 73% yields. It's a stable crystalline solid, so they were happy #ACSSpring2022

Improved the reaction to scale up, got multi kg scale, lots of this stuff for studies #ACSSpring2022

Limburg is summing up now--the compound they developed, PF-07038124, has desired pharmacology, has high in vitro clearance, and has a good synthetic route that can be scaled up well #ACSSpring2022

Have progressed through Phase 1, and completed a Phase 2A study last year, dosed for 6 weeks at 0.01%, there was a significant difference and it was well tolerated by both healthy and affected patients. Phase 2B study is coming later this year #ACSSpring2022

Limburg is thanking lots of people now, and the lovely audience #ACSSpring2022

Q: selectivity issue--has this borale been evaluated for other potential mechanisms, and did you worry about selectivity and evaluate it? #ACSSpring2022

A: we got what we were looking for #ACSSpring2022

Q: why did you target the phosphodiesterases #ACSSpring2022

A: based on what we already knew for past compound, we thought this was the best way forward #ACSSpring2022

Q: in different context, could oxyborale be made stable? #ACSSpring2022

A: ¯\_(ツ)_/¯ (I'm paraphrasing) #ACSSpring2022

Q: boronic acid accumulates in testes, was that a concern? #ACSSpring2022

A: I don't recall any concerns

Q: Can you comment on any phototoxicity liabilities you needed to de-risk for topical use?

A: We keep that in mind, but can't recall any problems

Q: Could you elaborate on resistance of hydrolysis the initial pinacol b ester? Any success for swapping to amino boronate salts to drive the eq?

A: for the 1 st part, we didn't think of that, for 2nd part, it was stable #ACSSpring2022

Taking a 10 min break, back at 1 pm est #ACSSpring2022

Hi! We’re back for the 2nd half of the 1st disclosures session #ACSSpring2022 MEDI division. It runs from 1 pm to 2:55 pm eastern time.

First up is Nuria Tamayo from Amgen, talking about a cancer drug to treat chromosomally unstable tumors #ACSSpring2022

The title is “Discovery of AMG 650, a first-in-class KIF18A inhibitor for the treatment of chromosomally unstable cancers” #ACSSpring2022

Kinesins are ATP dependent molecular motors involved in microtubule (MT) based functions. Most are mitotic kinesins #ACSSpring2022

Want to target it bc chromosomal instability are associated with genetic alterations in key cancer pathways (e.g. p53, BRCA, RB/Cyclin E1). #ACSSpring2022

Caused by error in division in mitosis. Can see this in breast and ovarian cancers #ACSSpring2022

Want to id a tool they can use to look at the role of KIF18A inhibition #ACSSpring2022

Took a library of analogues, found that spiro cyclopropyl piperidine made the compound more potent #ACSSpring2022

Putting in an amino alcohol improved the compound activity 5x more #ACSSpring2022

Used an expanded cancer cell panel to study this, looked at toxicity to normal cells, and if the cells died due to mitosis #ACSSpring2022

Treated a number of different cell lines with compound 3, only some are sensitive to KIF18Ai inhibition #ACSSpring2022

When treated with a cytotoxic agent, all the cell lines had a reaction #ACSSpring2022

Treated breast and ovarian cancer cells with compound 3, some were sensitive and some were insensitive #ACSSpring2022

Wanted to understand if compound 3 would also have an effect on bone marrow cells. They found that it did not have an effect while the cytotoxic agents did kill bone marrow cells #ACSSpring2022

Next looked in vivo, looked at 3 compounds, oxidative metabolism was the main pathway #ACSSpring2022

Compound 4 had good potency, was stable in microsomes, but it wasn't very orally available #ACSSpring2022

Subbed in a pyridine morpholino, and changed amine side groups, gave the oral availability they wanted. This was advanced to the next stage #ACSSpring2022

After 8 h, the compound was affecting mitosis, but this was gone after 24 h #ACSSpring2022

We decided that compound 5 couldn't go on to more studies, because it wasn't effective enough. So what kind of pharmacokinetic profile do they need? #ACSSpring2022

KIF18A only active in cells going through mitosis, but only 20% of cells are in this phase at any time. Also decided that they needed sustained activity to get cell death, more than 12 h #ACSSpring2022

Looked at different doses or ways to give the drug to see if they could get to the sustained activity they needed #ACSSpring2022

They dosed a small subset of compounds to mice, found that compound 8 was the closest to what they were looking for #ACSSpring2022

Compound 8 had right profile to be advanced to efficacy study #ACSSpring2022

Did animal model tumor model, found that the high dose stayed around for more than 24 h, tumor have increase in number of mitotic cells #ACSSpring2022

Wanted to get a compound to clinic to use orally, so looked at how the compound was metabolized. Found that oxidation was the main route. #ACSSpring2022

Then modified the left hand side of the molecule. Varying N, O, and F groups on the cyclic parts #ACSSpring2022

Compound 12, a difluoro compound, gave best oral availability #ACSSpring2022

This was their clinical candidate, AMG 650 #ACSSpring2022

that was a horrible drawing on my part, apologies. None of my organic profs from undergrad are allowed to look #ACSSpring2022

They predicted AMG 650 would have good oral availability and effectivity in humans. It's now in clinical trials #ACSSpring2022

Now Tamayo is pulling out the synthetic heavy slides #ACSSpring2022

They weren't able to crystallize any of these compounds bound to the enzyme. They thought it might bind to the enzyme itself, but the tubulin complex #ACSSpring2022

Oh yep, that worked. They got a xtal structure of their compound with the KIF18A tubulin complex. AMG 650 binds in a hydrophobic pocket #ACSSpring2022

The compound uses H bonds in sulfonamide chain #ACSSpring2022

That's the end! Questions now #ACSSpring2022

Q: what's the role of cyclopropyl on the piperadine? #ACSSpring2022

A: something about magic #ACSSpring2022

So I just typed out a long question and answer and then accidentally deleted it. It's gone now #ACSSpring2022

Moving on! #ACSSpring2022

Next up is Thomas Dineen from Blueprint Medicines, talking about a drug for treatment-resistant non small cell lung cancer #ACSSpring2022

Title: Discovery of BLU-945, a non-covalent, wild-type sparing, and reversible EGFR inhibitor for treatment-resistant EGFR+ T790M (with or without C797S) driven lung cancer #ACSSpring2022

They're looking at EGFR inhibitors, which are "A substance that blocks the activity of a protein called epidermal growth factor receptor (EGFR). EGFR is found on the surface of some normal cells and is involved in cell growth," says cancer.gov #ACSSpring2022

Compounds bind into the active site of ATP #ACSSpring2022

Compounds that can block the double mutants goes through a covalent bond in the pocket #ACSSpring2022

No available targeting therapies for people who have a triple mutant here #ACSSpring2022

Osimertinib has been approved for this, but it leads to on target resistance #ACSSpring2022

Inhibitors of wild type EGFR can lead to GI and skin issues, and sometimes can't be used in combination therapy #ACSSpring2022

So they wanted to "develop a non covalent, wild type and kinome sparing inhibitor of EGFR TM mutants for
the treatment of triple mutant EGFR driven NSCLC in mono and combination therapy" #ACSSpring2022

There are examples of reversible inhibitors of EGFR+ TM mutants, so started with compounds that had things in common with these #ACSSpring2022

Got a few hits from their libraries, but compound that was selective and stable also wasn't super potent #ACSSpring2022

They used this as their starting point, and tried to make it sit better in the pocket. Adding a F improved potency, but other modifications didn't help much #ACSSpring2022

Making the side chain a cycle to make naphthyridine made potency better in their cellular assays #ACSSpring2022

This compound had high selectivity for the EGFR mutants, but still wanted to make more potent #ACSSpring2022

Genetech had previously figured out the binding mode, so were able to improve the binding pocket by playing with F and CH3 groups #ACSSpring2022

Needed to get the compound closer to the Leu792 residue so disrupted H bond of an amine #ACSSpring2022

Making the amine cyclic was able to reduce the off target activity #ACSSpring2022

Adding a CH3 at 2 position bumped up potency. Tried to add polar compounds to make more stable, but that didn't work well, and made the activity go down #ACSSpring2022

Played with the 3 position of the azetidine, most replacements didn't make more stable, but a sulfone made the compound more stable and potent #ACSSpring2022

Changing around the sulfone-azetidine gave better potency and selectivity, but cleared from the rat model too quickly #ACSSpring2022

Changed around the quinoline core some more, removed the core nitrogen, made the clearance and availability better, methyl addition made more potent #ACSSpring2022

Monkey models showed that phase 2 metabolism increased the clearance of the molecule #ACSSpring2022

They wanted to reduce glucuronidation, found they could get there by making compound more sterically bulky, or alkylating the alcohol. #ACSSpring2022

Knew it was tolerated from earlier research, but it made clearance higher. So they added more polar compounds to the compound, and got what they were after #ACSSpring2022

Then they got to their compound BLU-945 #ACSSpring2022

Man, I have ugly S groups today

The compound is selective to EGFR-TM mutants, and made the tumors smaller in LRTM models #ACSSpring2022

Saw regressions at the higher dose without body weight loss. #ACSSpring2022

In triple mutant models, high doses lead to tumor regression #ACSSpring2022

In one case, a combo of osimertinib and BLU-945 led to tumor regression #ACSSpring2022

They moved BLU-945 onto a candidate #ACSSpring2022

In 1st patient that got 25 mg dose, BLU had long half-life and low clearance #ACSSpring2022

More clinical data is to come in the future #ACSSpring2022

Had some synthetic issues with the stereospecific synthesis of the azetidine, and making the isoquinoline core #ACSSpring2022

Summary! Cyclizing compound improved stability and potency, added ether made less potent but stayed in system better #ACSSpring2022

Thank you slide #ACSSpring2022

Questions! what was the main route of metabolism of your compound? #ACSSpring2022

A: it gets very chewed up #ACSSpring2022

Q: potencies are all about the same. That's rare for this kind of inhibitor. Can you comment? #ACSSpring2022

A: run assays at 1 M ATP #ACSSpring2022

Q: my wife has breast cancer, I saw what happened in regard to treatment. It's not just medication. Not complete information. If somebody has a lot of cancer, irritation can come up with radiation of system. Does radiation have an impact on the compound?

Q cont...the tissue is different after radiation #ACSSpring2022

A: radiation should have no effect on a small molecule kinase inhibitor #ACSSpring2022

Ok next speaker! Last up is Rebecca Davie from KalVista Pharmaceuticals to talk about a drug to treat hereditary angioedema, a rare disease that causes swelling in the body #ACSSpring2022

Title: Discovery of KVD900: A potent and selective small molecule plasma kallikrein inhibitor featuring a novel P1 group, as a potential oral on-demand treatment for hereditary angioedema #ACSSpring2022

plasma kallikrein is a trypsin like serine protease #ACSSpring2022

hereditary angioedema causes painful and potentially fatal swelling in the body, esp when it affects the throat and intestines #ACSSpring2022

Injectable PKa inhibitors have been shown as safe, but there are no oral on-demand drugs #ACSSpring2022

Earlier intervention can reduce swelling and pain #ACSSpring2022

Compound needs to be absorbed quickly and absorb the plasma kallikrein (that's what PKa is) #ACSSpring2022

They found a hit without a highly basic P1 group #ACSSpring2022

In a rat system, could give orally, had robust chem and good clearance #ACSSpring2022

Had five membered rings in core group, and various amines at P1 part. Made a matrix to figure out which combination was best #ACSSpring2022

The P1 had a benzylamine, which made the affinity better and reduced clearance. Wanted to move away from highly lipophilic compounds #ACSSpring2022

Put in an aminoisoquinoline, it matched the potency of the benzylamine P1 section. Yay because it was less basic #ACSSpring2022

Ended up adding an ether group to middle pyrazole, found that it was toxic to the kidneys in monkeys #ACSSpring2022

Added a chloroazaindole at the end, this chlorine addition was important for potency and selectivity of the compound #ACSSpring2022

Looked at substituted phenol groups to further find more neutral P1 groups, found that di-ortho substitution made compounds more potent #ACSSpring2022

In the S1 pocket, compound is displacing a water #ACSSpring2022

Put in rat model, had good oral availability, clearance #ACSSpring2022

Found KVD900, structure coming hang on #ACSSpring2022

KVD 900 structure #ACSSpring2022

In Phase 2 program, patients had single dose of KVD900 in the clinic, showed rapid protection #ACSSpring2022

Had a positive Phase 2 clinical trial, was safe, well tolerated, and effective #ACSSpring2022

The Phase 3 trial has started #ACSSpring2022

Thank you slide now #ACSSpring2022

Q: P1 pocket, methoxy is for lipophilic pocket, did you look for something that would fill this well? #ACSSpring2022

A: Yes, but everything else made the potency go down #ACSSpring2022

There was supposedly an online question but I can't see it in the chat #ACSSpring2022

That's it! Thanks everybody! #ACSSpring2022

#ACSSpring2022

nope, that had a couple of CH3 groups where F groups should be. The correct structure is below