Thread by @cenmag

Hello @LeighJKBoerner here, C&EN organic and medicinal chemistry reporter. I’m live tweeting the First Disclosures of Clinical Candidates from the #ACSSpring2021 MEDI division. It runs from noon to 3 pm et, and then again from 4 to 5:40 pm.

Session presider Nicole Goodwin from @GSK has now started her introduction. Everybody ready?

Nicole Goodwin is thanking everyone online for tuning in. We at C&EN would like to thank y'all for following along.

First up we have Ashvinikumar Gavai, Senior Director, Bristol-Myers Squibb, talking about clinical candidate BMS-986299, a potential cancer drug that targets the NLRP3 inflammasome #ACSSpring2021

T cell checkpoint inhibitors work in a variety of cancers, but not for everybody. The NLRP3 inflammasome pathway may work better. #ACSSpring2021

Chemical starting points for NLRP agonist program are imiquimod derivatives. They are small molecules with low molecular weight, and a stable rigid scaffold #ACSSpring2021

In new molecules, don’t want any immunosuppression, and don’t want to change the 4 position at the imidazoquinoline because that’s needed for the NLRP3 activity #ACSSpring2021

They can knock out the unwanted activity by adding hydrophilic groups at the 2 position, such as an propyl alcohol #ACSSpring2021

To make the candidate more potent, the researchers focused on R7 and R8 position. By replacing H with phenyl, compound becomes over 100x more potent #ACSSpring2021

Putting pyrazoles at the R7 position also increased the agonist activity #ACSSpring2021

Replacing the phenyl group with a pyrazole gave the best hNLRP3 agonist activity and selectivity, and reduced the activity they did not want. #ACSSpring2021

led them to the final BMS-986299 structure

The SMILES string for this molecule: CCN(C(C)=O)CC1=NC2=C(N)N=C(C=C(C3=NNC=C3)C=C4)C4=C2N1

Was made in 22% overall yield

Has dose dependent activity against mouse IL-1β, IL-18 #ACSSpring2021

When BMS-986299 injected into mouse with tumors, saw high antitumor activity, led to localized increase of IL-1β #ACSSpring2021

All the mice had their tumors disappear after treatment with BMS-986299, and rejected new tumor cells, suggesting that the treated mice had developed immunological memory #ACSSpring2021

Used two tumor models CT26 CRC and B16-F10 melanoma murine tumor models; researchers saw increase in survival rate in both tumor models after treatment with BMS-986299 #ACSSpring2021

Complete responses with addition of BMS-986299 and anti-PD1, goes up to 73% cures #ACSSpring2021

Clinical evaluation is ongoing into BMS-986299 by itself or in combination with Nivolumab and Ipilimumab for patients with solid tumors #ACSSpring2021

Question: How much activation are you looking for? Answer: we have seen no side effects so far. Are staying with the same dosing in the tumor #ACSSpring2021

Question: Is NLRP3 the direct target? We believe so, but we don’t have any specific data to show binding. #ACSSpring2021

Now here’s Tianbao Lu, Research Fellow, Janssen Research and Development, talking about JNJ-67856633, a potential cancer drug that goes after the MALT1 protease MALT1 protease #ACSSpring2021

running to keep up with this one, sorry for lack of detail

JNJ-67856633 highly bioavailable in both mouse and rat tumors, and it can be dosed once a day #ACSSpring2021

JNJ-67856633 is currently in phase 1 clinical trial. They have id’ed it as a combination partner with Bruton’s tyrosine kinase (BTK) inhibitor, and a Phase 1 study in combination with a BTK inhibitor is underway #ACSSpring2021

Next up is Ivan Efremov, from Fulcrum Therapeutics. He’s presenting clinical candidate FTX-6058 to treat sickle cell disease, which targets the EED (Embryonic Ectoderm Development) subunit of the PRC2 complex. Read more about it here acs.org/content/acs/en… #ACSSpring2021

Taking a 5 min break before his presentation, brb

here's the SMILES string O=C(NC1=CC(C(F)(F)F)=NC=C1)C(C=N2)=C(C(F)(F)F)N2C3=CC=CC4=C3C=CNC4=O

Ok we are back with Ivan Efremov, the Senior Director and Head of Medicinal Chemistry at Fulcrum Therapeutics #ACSSpring2021

This presentation will be available on the website later, Efremov says #ACSSpring2021

That’s the Fulcrum website: fulcrumtx.com #ACSSpring2021

Sickle cell is caused by a mutation in the adult hemoglobin gene, HbA. The mutated form is known as HbS. It undergoes polymerization in the deoxygenated state. #ACSSpring2021

There’s also fetal hemoglobin, called HbF #ACSSpring2021

The more fetal hemoglobin expressed in a person, the fewer problems people will have with sickle cell disease. #ACSSpring2021

Fulcrum id’d targets through CRISPR, found EED (Embryonic Ectoderm Development) as important part of target #ACSSpring2021

FTX-6058 binds EED, ligands bind site contains electron deficient Arg, plus 3 electron rich aromatic rings, on Phe97, Tyr148, and Tyr365 #ACSSpring2021

Early on, azolopyrimidine compounds showed promise, but the potency and other parameters were not ideal #ACSSpring2021

Looking at a macrocyclization approach, which has several upsides, but the synthesis can be complicated #ACSSpring2021

Thought about intramolecular cyclization, and 4 scaffolds looks good, but one stuck out as the best scaffold #ACSSpring2021

Finding a good way to cyclize the molecules was time consuming, and used Suzuki coupling as the last step #ACSSpring2021

The macrocyclic analogues bound better to EED than the non-cyclic compounds #ACSSpring2021

FTX-6058 #ACSSpring2021

SMILES string CC1=NC=CC=C1C2=CC3=C(NCC4=C(F)C=CC5=C4[C@@H](CO3)CO5)N6C2=NN=C6

Synthesis took 16 steps, was scalable #ACSSpring2021

Screening showed robust binding to EED, has good clearance values, clean safety profile #ACSSpring2021

In vitro profiling, FTX-6058 showed high HbF induction, in both healthy cell donors, and also in donors with sickle cell disease #ACSSpring2021

Researchers saw 2-3 fold increases in fetal hemoglobin (HbF) when treated with FTX-6058 #ACSSpring2021

Human dose projections, once a day dosing, predicted dose is 4 mg #ACSSpring2021

Researchers are currently enrolling volunteers in phase 1 clinical study #ACSSpring2021

Taking a 3 min break, then back with the next presenter, Grace (Chihyuan) Chuang, the Director of Medicinal Chemistry at Cytokinetics #ACSSpring2021

Up last for the first session is Grace (Chihyuan) Chuang, Director of Medicinal Chemistry at Cytokinetics. She’ll be talking about candidate CK-274, a cardiac myosin inhibitor that could potentially treat genetic hypertrophic cardiomyopathies. #ACSSpring2021

This is a rare, inherited disease that causes heart muscles to thicken. #ACSSpring2021

Heart disease is #1 cause of death, there are over 6 million americans with heart failure #ACSSpring2021

1 in 500 humans that could lead to HCM, only 1 in 3200 develop HCM. can result in stroke and sudden death. There is surgery to treat, but it’s invasive. Existing medicines have significant side effects. #ACSSpring2021

HCM is hypertrophic cardiomyopathy, btw. #ACSSpring2021

Speaker is showing a pretty cool vid of muscles contracting the heart, sorry can't show y'all #ACSSpring2021

Theory is that if they can slow down cardiac myosin, which may allow heart muscles to properly relax #ACSSpring2021

Mavacamten, was first in class CSI cardiac sarcomere inhibitor, but does not reach a steady state concentration in people until about 6 weeks, which makes it easier to overdose on drug. New class should have a steady state within 2 weeks #ACSSpring2021

In trying to get better metabolic stability, the researchers changed up the linker with indoline and aryl substituents. Looked at the binding pocket and designed molecules that could better fit
#ACSSpring2021

They replaced the phenyl, saw higher turnover, and the potency stayed the same. Also found that the R isomer is preferred in synthesis, and the S-isomer was inactive even in high concentrations. #ACSSpring2021

Oxadiazole substituent, most small substituents tolerated, ethyl the best, this substituent has best potency #ACSSpring2021

Compound showed efficacy in both small and large animals. #ACSSpring2021

9 steps with 36% overall yield, can get amine in the large scale, over 500 g. Showed efficacy in both healthy and diseased animals #ACSSpring2021

In healthy volunteers, CK-3773274 reached steady state in about 14 days #ACSSpring2021

Early data shows that the dose might be flexible in people. Phase 2 trial is fully enrolled, hope to have data this year. #ACSSpring2021

That’s it for First Disclosures of Clinical Candidates for now. Thanks for following along, and see you again at 4 pm et. #ACSSpring2021

Our reporter @RLCscienceboss reported on the NLRP3 inflammasome recently cen.acs.org/pharmaceutical…

Coming back for the 2nd session of First Disclosures of Clinical Candidates in just a few. Are we ready? Are we psyched??

FYI, these sessions will be available on demand from April 19 to April 30, for those who registered for the meeting. #ACSSpring2021

Once again, this is @LeighJKBoerner, C&EN organic and medicinal chemistry reporter. I’m live tweeting the First Disclosures of Clinical Candidates from the #ACSSpring2021 MEDI division. 2nd session is from 4 to 5:40 pm.

Hi everybody, we’re back for part deux of First Disclosures of Clinical Candidates from the #ACSSpring2021 MEDI division

For the first presentation in this second session, Michael Siu, Senior Scientist of Medicinal Chemistry at Genentech will be presenting clinical candidate GDC-0134, a potential treatment for amyotrophic lateral sclerosis (ALS), aka Lou Gehrig’s disease. #ACSSpring2021

GDC-0134 is a small molecule inhibitor, and targets the dual leucine zipper kinase (DLK) #ACSSpring2021

ALS patients usually die within 5 years of diagnosis, there are only 2 approved drugs for ALS #ACSSpring2021

Since this is a neurodegenerative disease, drugs have to pass through the blood brain barrier #ACSSpring2021

Screened against kinase database, selected 2 hits, needed to change some groups due to toxicity issues #ACSSpring2021

Used DLK X ray structure to see that the candidate fits well into the binding pocket #ACSSpring2021

Tested in mouse model, found that their compound could suppress the DLK pathway #ACSSpring2021

Looked at a second compound for further follow up, binds in morpholine ring system #ACSSpring2021

Wanted to add potency, but needed to add lipophilicity, so needed to change the ring system #ACSSpring2021

Added a bridged morpholine ring, compound showed increased potency #ACSSpring2021

This fit well in active site, but is missing several possible groups to help it better bind. This improved kinase selectivity #ACSSpring2021

GDC-0134 #ACSSpring2021

Several ways to synthesize GDC-0134. The researchers used in a mouse model with damaged optical cells, compound kept them from undergoing apoptosis #ACSSpring2021

Proceeded in toxicity study, and got IND and Phase 1 human study #ACSSpring2021

Phase I study of GDC-0134 in patients with ALS is finished, but group has decided not to keep going on the clinical development #ACSSpring2021

Still think DLK is good as a target, and hope to keep studying for neurodegenerative disease #ACSSpring2021

Question: does GDC-0134 reverse disease or merely slow progression? Answer: We see slowing of disease #ACSSpring2021

Question: what’s the solubility of the compound? Answer: It’s a weak base, almost neutral, so solubility is on lower end #ACSSpring2021

That's it for that talk, moving onto the next #ACSSpring2021

Last up for the day is Timothy M. Caldwell, Principal Investigator from Deciphera Pharmaceuticals. He’s talking about clinical candidate DCC-3014, aka vimseltinib, a potential cancer treatment that targets colony-stimulating factor 1 receptor (CSF1R) kinase. #ACSSpring2021

Problems with CSF1R signaling is found in several disease states, eg cancer, Alzheimer's and Parkinson's disease #ACSSpring2021

When CSF1R is ‘switched off’, it blocks the approach of ATP to the protein #ACSSpring2021

There’s what they’re calling the “kinase switch pocket.” It has 2 areas that they could take advantage of to change kinase selectivity #ACSSpring2021

They made over 1000 compounds to approach this problem, just talking about pyrimidinones today (whew says the person drawing the molecules, aka me) #ACSSpring2021

Added a methyl group at the 3 position at pyrimidone, didn’t change the activity at CNFIR #ACSSpring2021

The presence of the 2 methyl pyridine core gave high kinase selectivity and inhibited CSF1R #ACSSpring2021

Got a xtal structure so were able to look at the binding in the pocket, there were 4 important H bonds formed between this compound and CSF1R #ACSSpring2021

Compound 11 forced CSF1R into a confirmation that mimics the ‘switched off’ state #ACSSpring2021

The researchers found 19 H bonds with CSF1R, holding it tightly in this switched off state #ACSSpring2021

Found a lot of good compounds, but one worked much better than the rest. Even at low doses, saw over 70% inhibition of CSF1R #ACSSpring2021

Good solubility at pH 2, there were no issues with permeability, and it was very stable across all species they tested. It also had excellent bioavailability in animal studies #ACSSpring2021

Made this compound their pre-clinical candidate, DCC-3014 #ACSSpring2021

Performed well, probably because of the high number of H bonds #ACSSpring2021

“This is probably one of the most selective kinase inhibitors known,” Caldwell said #ACSSpring2021

DCC-3014 inhibited growth and colorectal tumors by itself and also given in tandem with anti-PD-1, and also reversed immunosuppression in mouse colorectal cancer model #ACSSpring2021

DCC-3014 showed protection against prostate cancer in a cancer bone invasion mouse model #ACSSpring2021

In clinical studies, DCC-3014 used against tenosynovial giant cell tumors (benign) in wrists, fingers, ankles and toes #ACSSpring2021

Phase 1 results showing that the compound is being tolerated by patients, and is having anti-tumor activity, study includes 22 patients #ACSSpring2021

Case studies: 57 year old female, showed a partial response after 2 cycles, had a 67% decrease in tumor volume at cycle 16 #ACSSpring2021

Another case study: 39 year old female, TGCT in knee, has has a partial response after 2 cycles, 41% decrease in tumor #ACSSpring2021

The Phase I/II study is ongoing, currently enrolling 60 patients. They expect an update of the Phase I/II data in TGCT is expected in the 2nd half of 2021 #ACSSpring2021

Question: is the interaction of methyl with pyrazole, is it the CH or the pyrazole? Answer: The pyrazole. it’s strange, but it’s real #ACSSpring2021

Presider Nicole Goodwin pointed out that 3 out of the 6 compounds presented today were pyrazoles. “Pyrazoles for the win,” she said. #ACSSpring2021

Aaaaaand that’s all, everybody! Thanks for following along. Look out for my story on this session on Monday. Have a great weekend! #ACSSpring2021

#ACSSpring2021