The October edition of Small Molecules of the Month includes several potential best-in-class clinical candidates including but not limited to a second-gen LPA1 antagonist from BMS, two muscle modulators from Cytokinetics, and a Janssen pan-genotype, pan-serotype Dengue virus inhibitor. There are several interesting modalities including an oral macrocyclic peptide from Merck, a tumor-specific prodrug from BMS, and a CRBN-based degrader that no-longer needs two imide motifs from St. Jude. As always, there’s plenty of interesting chemical groups – a hydrazine, furenone, pyrrole, decalin, strained macrocycle, quaternary ammonium, … enjoy!

Full summaries, a PDF download, and links to articles are below. Reviewer Joachim Rudolph also points us in the direction of MRTX1133, a potent KRAS G12D inhibitor which was recently disclosed at an AACR-NCI-EORTC virtual conference, but has not been published yet. Our team is working on new ways to keep you updated beyond publications though, stay tuned!

BMS986278 – BMS LPA1 antagonist
compound 4c – St. Jude phenyl-glutarimide CRBN-based degrader
AS-0141 – Carna Biosciences CDC7 kinase inhibitor
aficamten – Cytokinetics myosin inhibitor
CP-628006 – Pfizer CFTR potentiator 
reldesemtiv - Cytokinetics troponin activator
JNJ-A07 – Janssen dengue virus inhibitor
eliapixant – Bayer P2X3 antagonist
repotrectinib - TRK inhibitor
compound 10 – BMS tumor-activated TGFBR inhibitor 
venglustat – Sanofi GCS inhibitor 
maralixibat – Mirum IBAT inhibitor
compound 44 – Merck PCSK9 inhibitor
compound 1 – Janssen allosteric HPK1 inhibitor

Small Molecules of the Month - Oct. 2021

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  1. This month’s cover molecule, BMS-986278, is an LPA1 antagonist and oral (up to 125 mg BID) Ph. II clinical candidate for idiopathic pulmonary fibrosis (IPF) (NCT04308681). Reviewer and nominator Christian Kuttruff says: “While there are two approved molecules for the treatment of IPF (pirfenidone from Roche and nintedanib from BI), there is still a significant medical need for IPF/PF-ILD patients. Alongside current Phase III assets targeting IPF (Fibrogen’s pamrevlumab, Roche’s pentraxin and United Therapeutics’ teprostinil), this BMS LPAR1 antagonist is a promising compound in development for IPF due to the fact that their previous frontrunner molecule (BMS-986020) showed promising proof-of-efficacy in a 6 month Ph. II trial in IPF patients, slowing the decline of FVC by 69% vs. placebo. BMS-986020’s trial was stopped due to hepatobiliary toxicity, which BMS-986278 may address.”

    “The hepatobiliary tox. is believed to be an off-target effect specific to BMS-986020, which can most likely be attributed to increased plasma bile acids, possibly due to the fact that the compound has significant inhibitory activity at several key bile acid transporters (incl. BSEP, MRP4, MDR3). Their chemical optimization approach therefore included a decrease in lipophilicity and increase in C(sp3) to decrease transporter inhibition and a lower dose via replacement of the amino-isoxazole carbamate which was metabolically labile. By systematically optimizing the individual parts of the molecule (going from biphenyl acid to 3-oxycyclohexyl acid; phenyl-ring to methyl-pyridine, isoxazole to polar methyl-triazole and installation of optimal O-carbamate) they ended up with BMS-986234 which has reduced clogP, increased PSA and increased C(sp3) vs. BMS-986020, which resulted in the improved liability profile (particularly protein binding & bile salt export pump activities).”
  1. The bifunctional degrader, SJ995973, was nominated by Joachim Rudolph. “Instead of the thalidomide-based cereblon binder present in the established BET degrader tool dBET1, SJ995973 uses a novel cereblon binder containing a simple phenyl ring instead of the hydrolytically labile phthalimide group. Not only is SJ995973 an extremely potent BET degrader (BRD4 DC50 = 0.87 nM (Dmax = 99%)), but the alternative cereblon binder offers key advantages over thalidomide (and classical IMiDs used in PROTAC design in general), including chemical stability, smaller size and TPSA, and synthetic feasibility.” This novel cereblon binding motif is likely to be reused in many new applications.
  2. The Carna Biosciences CDC7 kinase inhibitor, AS-0141, is a clinical candidate for cancer with a structure that contains a hydrazine, furenone, and ester, all rare functional groups for an oral molecule. The molecule has a long residence time on the kinase, and despite a short half-life in mouse, extended target engagement is observed >24 h post-dose. The unusual structure of the molecule was confirmed by single crystal X-ray diffraction. This is also an interesting example of a drug candidate being developed by a drug discovery product supplier – reagents for some of the assays used were supplied by Carna Biosciences’ assay products division.
  3. The Cytokinetics next-generation myosin inhibitor, aficamten, is a phase II candidate for genetic hypertrophic cardiomyopathies, and is orally dosed between 5-30 mg QD. It follows BMS’s mavacamten (acquired from Myokardia in a $13.1B deal), whose NDA is under review by the FDA. This class of molecules is intended to address hypertrophic cardiomyopathy (in which thickening of the left ventricular walls limits cardiac output) by inhibiting cardiac sarcomere contractility. The molecule is reaches steady state within two weeks of dosing in a Ph. I trial rather than over six weeks for mavacamten, is safe and well-tolerated in healthy volunteers, and has low risk of DDIs with no significant cytochrome P450 induction or inhibition risk. The indoline starting point was discovered in a high-throughput phenotypic screen using bovine cardiac muscle myofibrils measuring the rate of ATP hydrolysis. Selectivity against cardiac myofibrils was inherent to the scaffold, with no measurable inhibition against smooth muscle myosin detected throughout optimization. This is an excellent modern example of empirical screening being employed boldly and successfully for a novel mechanism, with the follow-through to a clinical molecule.
  4. The Pfizer CFTR potentiator, CP-628006, enhances CFTR function in cystic fibrosis patient-derived airwell cells with a distinct mechanism of action from existing potentiators such as ivacaftor. It has a unique chemical structure, and in contrast to other potentiators does not seem to inhibit the channel at high concentrations of drug and appears to improve the plasma membrane stability of F508del-CFTR rather than destabilize it. Greater clinical benefit in CF might be achieved with combinations of different classes of potentiators such as CP-628006, making it an interesting albeit synthetically challenging starting point for further investigation.
  5. The Cytokinetics second generation troponin activator, reldesemtiv, is intended to treat muscle weakness by directly activating skeletal muscle. A high concentration of free drug is expected to be needed due to the large amount of fast skeletal muscle troponin in the body, making safety and selectivity critical. Reldesemtiv demonstrated robust activity in a Ph. I PD assessment of muscle response (with a maximum conc. reached at 4000 mg dose of 26 μM) and a reduction in decrease of ALSFRS-R scores in a Ph. II study for ALS patients with more advanced disease across all dose groups, supporting its advancement to a Ph. III trial despite the primary endpoint of slow upright vital capacity not being achieved. The molecule looks quite different from its thiadiazole starting point identified by HTS, and the focus of optimization was on improving selectivity and distribution to muscle rather than brain tissue since the first-generation molecule tirasemtiv caused what appear to be off-target CNS effects. Chemically the molecule is an interesting example of a pyrrole and fluoro-cyclobutane-containing drug candidate, and is completely structurally different from first-generation molecule. Development-wise, the molecule is also a good example of a molecule succeeding in human despite high rodent clearance (particularly in male rather than female rats). The drug is another example of a fascinating and bold mechanism of action being pursued with a small molecule by Cytokinetics.
  6. The Janssen pan-genotype, pan-serotype dengue virus inhibitor, JNJ-A07, demonstrates broad activity against a panel of 21 clinical isolates and has a high barrier to resistance. It blocks the interaction between the non-enzymatic NS4B protein and NS3, preventing them from forming an NS3-NS4B complex which is essential for replication (though it does not appear to dissociate formed NS3-NS4B complexes). The mechanism is another recent success for phenotypic screening and if developed, this class of molecules could be a significant tool against dengue disease, which affects >96M individuals worldwide.
  7. The Bayer P2X3 purinoreceptor antagonist, eliapixant (BAY1817080), is intended to treat various disorders associated with hypersensitive nerve fibers, including endometriosis. The hypothesis is that P2X3 receptor antagonism can inhibit cycles of pain causing neurogenic inflammation, causing pain, etc. modifying the underlying disease in endometriotic lesions. Endometriosis is an area of significant unmet medical need but with a high bar for safety.  Eliapixant is highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. The molecule completed a phase I safety study and is in several ongoing phase II trials in different conditions including endometriosis (NCT04614246); other hypersensitive nerve fiber-associated disorders, including refractory or unexplained chronic cough (RUCC) (NCT04562155); diabetic neuropathic pain (DNP) (NCT04641273) and overactive bladder (OAB) (NCT04545580). Eliapixant given 75 mg BID appears to significantly decrease cough frequency in patients with refractory chronic cough.
  8. The Turning Point Therapeutics oral, brain-penetrant ALK/ROS1/TRK kinase inhibitor, repotrectinib (TPX-0005), is a macrocyclic molecule with a small size intended to limit adverse interactions with resistance mutation hotspots near kinase active sites. TRK fusion proteins are driver mutations in certain cancers (which respond well to larotrectinib and entrectinib) but resistance is anticipated to be a problem. This molecule inhibits TRKA, TRKB, TRC, ROS1, and various forms of ALK, and durable responses were observed in both TKI-naïve and pretreated patients with NTRK+ cancers (NCT03093116).
  9. The BMS TGFβR inhibitor prodrug, “compound 10,” demonstrates antitumor efficacy comparable to the parent compound (BMS-986260) in a syngeneic model with once-weekly dosing, while reducing the systemic exposure of BMS-986260. Reducing the systemic exposure of a TGFβR inhibitor is important due to previously observed mechanism-based cardiac toxicity. This prodrug is preferentially cleaved by proteases overexpressed in tumors, and results in a prolonged, favorable tumor-to-heart ratio of the active drug in distribution studies. This is an interesting proof-of-concept for tumor-targeted prodrugs as an approach to improving the therapeutic index of cancer drugs. It is especially interesting in the immune-oncology setting where the initiation of anticancer activity in a tumor may lead to an abscopal effect and broader systemic responses due to antitumor immune activation.
  10. The Sanofi glucosylceramide synthase (GCS) inhibitor, venglustat, is an oral, brain-penetrant clinical candidate for GBA-mutant Parkinson’s disease and other diseases where GBA-mutations are relevant. Though the molecule did not demonstrate efficacy within one year in early GBA-PD patients and was discontinued in this indication (NCT02906020), it continues to be tested in various rare genetic diseases including Gaucher disease type 3 (NCT02843035), Fabry disease (NCT02228460), GM2 gangliosidosis (NCT04421451), and autosomal-dominant polycystic kidney disease (NCT04705051), as its safety has already been demonstrated.
  11. The Mirum Pharmaceuticals IBAT bile acid transporter inhibitor, maralixibat, has a long history, having been first patented by scientists at Searle in 1994 and published by the time Searle became part of Pharmacia in 2005. It was finally approved in Sep. 2021 for treatment of cholestatic pruritis in patients with Alagille Syndrome, and is estimated to reach annual sales of $536M by 2026, a nice success story for repurposing of old mechanisms by a biotech. The drug is a bile acid transport inhibitor, preventing enterohepatic bile acid recirculation, and was originally designed to have minimal systemic exposure after oral administration.
  12. The Merck bicyclic macrocyclic peptide PCSK9 inhibitor, “compound 44,” is a highly potent (Ki = 0.00239 nM) and orally bioavailable (cyno %F = 2.9, t1/2 = 10 h) agent against a notoriously difficult target for small molecules, demonstrating target engagement comparable to approved PCSK9 antibodies. The discovery of this molecule is an interesting proof of concept for this emerging area of drug space (oral macrocyclic peptides), with hits generated by a relatively new technology (mRNA display screen) and advanced with structure-based design (potency increased by 100,000x). Several off-target issues were addressed while simultaneously lowering clearance, lipophilicity, and improving oral bioavailability. Interestingly, the clearance of the molecules was shifted over time from predominantly hepatic to renal by reducing OATP 1B1 transporter activity. This PCSK9 drug discovery campaign is a tour de force from the team at Merck and a must-read for anyone interested in bRO5 chemical matter.
  13. The Janssen non-ATP competitive HPK1 inhibitor, “compound 1,” was identified from a screening cascade specifically looking for allosteric inhibitors, which may provide a selectivity advantage over ATP-competitive starting points. Reviewer Adi Murthy says, “Specificity may prove challenging for HPK active site inhibitors since it belongs to a large family of Ste20 genes that act as MAP4Ks, all with high kinase domain homology.” Reviewer and nominator Callie Bryan says, “The publication summarizes work towards allosteric inhibitors of HPK1 targeting the inactive conformation through application of a cascade assay designed to target full-length, inactive HPK1. In doing so, molecules that attenuate autophosphorylation and potentially interfere with active HPK1 dimer formation were discovered without strong competition with ATP. This strategy could prove fruitful to other kinases where allosteric inhibition may provide higher likelihood of selective inhibition.”

Links to Articles:

  1. BMS986278 – BMS LPA1 antagonist
  2. compound 4c – St. Jude phenyl-glutarimide CRBN-based degrader
  3. AS-0141 – Carna Biosciences CDC7 kinase inhibitor
  4. aficamten – Cytokinetics myosin inhibitor
  5. CP-628006 – Pfizer CFTR potentiator 
  6. reldesemtiv – Cytokinetics troponin activator
  7. JNJ-A07 – Janssen dengue virus inhibitor
  8. eliapixant – Bayer P2X3 antagonist
  9. repotrectinib – TRK inhibitor
  10. compound 10 – BMS tumor-activated TGFBR inhibitor 
  11. venglustat – Sanofi GCS inhibitor 
  12. maralixibat – Mirum IBAT inhibitor
  13. compound 44 – Merck PCSK9 inhibitor
  14. compound 1 – Janssen allosteric HPK1 inhibitor

We hope this is useful. Explore for more drug discovery articles, and happy hunting! If your company would be interested in supporting Drug Hunter and our team in keeping our industry colleagues up-to-date, please contact our latest new hire and Operations Leader, Melissa Lynch, at [email protected]

Special thanks to Dr. Vinicius Texeira, Dr. Daniel Gedder, and Dr. Maria Koyioni for their assistance preparing this month’s article and our reviewers for their feedback.