Cerevance’s CVN293 is an oral, CNS-penetrant, selective inhibitor of potassium efflux-mediated NLRP3-inflammasome activation in microglia for the treatment of neurodegenerative disorders. Cerevance’s NETSseq platform was used to discover a microglia-specific potassium efflux channel, KCNK13, which allows modulation of the NLRP3-inflammasome in the CNS without affecting peripheral innate immunity. Read the full article to discover highlights on the CNS-penetration of highly polar compounds and how particle size can be key to oral bioavailability

Zilucoplan is a macrocyclic peptide-containing drug with 15 amino acids in total, targeting the challenging-to-drug C5 complement protein and formulated for self-administered once-daily SC injection. In Sept. 2023, zilucoplan received its first global approval in Japan, followed in Oct. 2023 by FDA approval for gMG patients who are AChR antibody-positive, making zilucoplan the first drug derived from mRNA display for cyclic peptides to be approved. This case study discusses how zilucoplan was discovered and why it’s an important scientific milestone for the industry.

Leniolisib is a selective PI3Kδ inhibitor that received approval in March 2023 from the FDA as a first-in-class treatment for activated PI3K-δ syndrome (APDS), a genetic immunodeficiency disorder caused by PI3Kδ activation. The leniolisib discovery program is notable for several reasons: it is a first approval for a PI3K inhibitor outside of oncology; the first approved drug for APDS; has a novel chemotype that appears to avoid safety issues that led to black box warnings seen with other PI3K molecules; and it overcame a polymorph issue with an early lead that led to inconsistent exposures.

Kymera's KT-474 is the first oral degrader to demonstrate activity in clinical trials outside cancer and Sanofi recently started a Ph. II trial with the molecule in AD, restoring life to IRAK4 as an immunology target. This article highlights why Kymera’s KT-474 program is scientifically notable, including how it differentiates from small molecule inhibitors, potential competitiveness with biologics, the first reported cryo-EM ternary complex of a heterobifunctional degrader, and why this 2023 Molecule of the Year Nominee will likely be considered a “landmark in drug discovery” for some time.

NT-0796 is NodThera's pro-drug inhibitor of the NLRP3 inflammasome. NT-0796 is currently in a Ph. Ib/IIa trial in obese individuals at risk of developing atherosclerotic cardiovascular diseases. NT-0796 has the potential to reduce neuroinflammation in Parkinson’s disease. The NLRP3 inflammasome has emerged as a hot target due to its connection to Alzheimer’s disease, Parkinson’s disease, gout, and other diseases. Here is a detailed review of the role of NLRP3 inhibition in treating atherosclerosis, how NT-0796 was identified and what makes it special, clinical development, and more.

RPT193, an oral, second-generation CCR4 inhibitor from RAPT Therapeutics, is in Ph. II clinical trials (400 mg QD) to treat atopic dermatitis (AD) (NCT05399368) and asthma (NCT05935332). CCR4 has been a long outstanding therapeutic target for treating inflammatory diseases, but despite many efforts, no molecule inhibiting this receptor has progressed beyond Ph. I for these indications.

JNJ-54175446 is an oral, CNS-penetrant P2X7 ion channel antagonist targeting a novel pathway linking neuroinflammation and depression, with recently published Ph. I data in major depressive disorder (NCT02902601, initiated in 2016). The Janssen program is notable as a pioneering early example of a neuroinflammation program started at a time before NLRP3 or neuroimmunology were commonly discussed topics, as they are today [...]

Jecure’s JT001 is a selective inhibitor of NLRP3 inflammasome and among the earlier compounds in this now highly competitive space. In 2018, Genentech bought Jecure Therapeutics for an undisclosed amount, gaining access to Jecure’s NLRP3 inhibitor JT001. While there are many other NLRP3 inhibitors now in the space, JT001 is an interesting example of an initial attempt to overcome liver toxicity with well-known NLRP3 inhibitor MCC950. However, the molecule ran into its own kidney toxicity issues, making this an intriguing toxicology case study.

Pfizer’s ritlecitinib, a first-in-class, selective, oral covalent inhibitor of JAK3 and the TEC family of kinases, was FDA-approved in June 2023 for the treatment of severe alopecia areata. Ritlecitinib derives its JAK-family kinase selectivity from the covalent modification of a unique cysteine on JAK3. This annotation reviews the discovery of ritlecitinib, highlighting the interpretation of selectivity assays, the PK optimization, the evolution of the JAK3 therapeutic hypothesis, and how this 2023 Molecule of the Year nominee has become a classic case study for covalent drug discovery.

PF-07054894 is a potential first-in-class, oral Ph. I clinical candidate targeting the chemokine receptor CCR6 for ulcerative colitis (NCT05549323). Several companies have pursued antibodies and small molecules targeting CCR6 or its endogenous ligand, CCL20 (e.g. GSK3050002) for immunological conditions including other preclinical squaramides (e.g. Galderma, Allergan, ChemoCentryx) and other series (e.g. Takeda), but PF-07054894 appears to be the first selective CCR6 antagonist to enter clinical development.

Genentech announced that fenebrutinib (GDC-0853), a non-covalent BTK inhibitor entering Ph. III, showed significant human CNS exposure and reduced new brain lesions in Ph. II for relapsing multiple sclerosis. Fenebrutinib is the only reversible BTK inhibitor in Ph. III for MS, and has the opportunity to differentiate on safety relative to covalent inhibitors. This case study highlights notable challenges overcome in the discovery of fenebrutinib including surprising metabolism, animal-specific on-target toxicity, and more.

PDE4 inhibitors have shown promise in a range of pulmonary, dermatological and neurological diseases, but have been hampered by side effects including emesis and diarrhea . Difamilast , originated by Otsuka , recently approved for the treatment of atopic dermatitis [...]

Indoleamine 2,3-dioxygenase 1 (IDO1) is an extrahepatic tryptophan-metabolizing enzyme which is believed to contribute to the evasion of the immune system by tumors , making it an attractive target for cancer immunotherapy, especially in combination with immune [...]

“PROTAC 6” (GlaxoSmithKline (GSK) IAP-based selective RIPK2 degrader with prolonged in vivo PD)

Zunsemetinib (ATI-450, CDD-450) is a p38α- MK2 complex inhibitor discovered by Confluence Technologies and developed by Confluence spinout, Aclaris Therapeutics. The molecule has a unique molecular glue-like mechanism of action that held promise in immunology, but sadly recent results have led to its discontinuation. This article reviews the target, its mechanism, and why it mattered.

Takeda Pharmaceuticals has announced positive results for TAK-279 in Ph. IIb for the treatment of moderate-to-severe plaque psoriasis (PsO). Just disclosed last year , TAK-279 (formerly known as NDI-034858) was acquired by Takeda from [...]

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2022, and the results are in. The 2022 winner, with the most overall votes across the ten finalist molecules , is BMS’ oral, deuterated allosteric TYK2 inhibitor, deucravacitinib, the first new treatment for plaque psoriasis in nearly a decade [...]

Preclinical validation for IRAK4 inhibitors for dermatology from activity in human biopsies. Interleukin-1 receptor-associated kinase ( IRAK4 ) is downstream of toll-like receptors (TLRs), which are established mediators of inflammation . Like many immune-signaling nodes (JAK, BTK), this has been of interest for potential treatment of [...]

In 2022, Amgen acquired ChemoCentryx for $4B in cash, primarily for avacopan, a first-in-class treatment approved in 2021 for a rare automimmune condition, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Scientifically, it is notable that avacopan is the first small molecule targeting the complement pathway to be [...]

IL-17 has been a hot target in immunology thanks to the clinical and commercial success of marketed anti-IL-17A and anti-IL-17RA antibody drugs secukinumab (Cosentyx), ixekizumab (Talz), and brodalumab (Siliq) in psoriasis, psoriatic arthritis, and ankylosing sponylitis. With the recent identification of small molecule binders of IL-17A [...]

Deucravacitinib (Sotyktu) is a first-in-class oral, allosteric tyrosine kinase 2 (TYK2) inhibitor, FDA-approved in September 2022 for moderate-to-severe plaque psoriasis. It is the first novel oral therapy for this indication in nearly 10 years, and is believed to potentially become the new standard of care. Deucravacitinib is the first de [...]

Today, ozanimod is a likely megablockbuster drug approved for ulcerative colitis and multiple sclerosis. But before it became the first S1P modulator approved in ulcerative colitis, it received a scary, headline-making “ Refuse to File ” letter from the FDA due to insufficient preclinical characterization of an active metabolite RP112273 [...]

GDC-2394 (Genentech) is an oral NLRP3 inflammasome inhibitor. The NLRP3 inflammasome is the best studied and most characterized inflammasome , with the protein playing a key role in the detection of inflammatory danger signals which are a hallmark of many inflammatory diseases. Hyperactivation of the NLRP3 has been implicated in the [...]

PI3 kinases are part of the PI3K/Akt/mTOR signaling pathway that is downstream of Receptor Tyrosine Kinases (RTKs), G-protein-coupled receptors (GPCR), and GTPases such as KRAS. Since their identification in the 1980s, and due to their central role in cancer, the therapeutic targeting of the phosphatidylinositol-3-kinase (PI3K), and more [...]

Context. “Compound 39 ” (RAPT Therapeutics) is a general control nonderepressible 2 (GCN2) protein kinase inhibitor. As the master regulator of the integrated stress response triggered by cellular stress in the tumor microenvironment, GCN2 has been implicated in tumor progression and immune escape, making the kinase an attractive oncotarget [...]

In September 2022, deucravacitinib (Sotyktu) , a first-in-class oral, allosteric tyrosine kinase 2 (TYK2) inhibitor for moderate-to-severe plaque psoriasis, was approved by the FDA. Aside from its first-in-class mechanism of action, it is the first approved de novo deuterated drug. This premium deep dive into deucravacitinib includes: the [...]

Context. ACT-660602 (Idorsia Pharmaceuticals) is an oral chemokine receptor CXCR3 antagonist being developed for autoimmune diseases. Chemokines and their receptors make up the signaling system that is responsible for immune cell migration. This is important for the innate immune system’s ability for fighting infection, but dysregulation of [...]

Context. “Compound 23” (Merck) is a selective oral cathepsin K (CatK) inhibitor intended for osteoarthritis. Osteoarthritis affects around 15% of the population, and current treatments offer only symptom relief, highlighting the need for targeted treatments. Prior to the “compound 23”, several CatK inhibitors had reached clinical [...]

Amgen has acquired ChemoCentryx in a deal that includes lead molecule avacopan (Tavneos), a first-in-class orally bioavailable small molecule complement 5a receptor (C5aR) antagonist approved as an adjunctive treatment to standard of care therapy for adults with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated [...]

This article is Part VI of a review series covering all the initial public offerings for the biotech and pharmaceutical industries in 2021. Pt. I and Pt. II provided an overview of 2021 IPOs by therapy area, technology, and therapeutic class. Pt. III and Pt. IV provided a deep dive into the 2021 IPOs for oncology-focused companies, while P.t [...]

Context. CC-99677 (BMS) is an oral, covalent MAPK–activated protein kinase-2 (MK2) inhibitor being developed for autoimmune diseases. Although p38 is the most heralded member of the p38-MAPK signaling pathway, one that mediates the release of pro-inflammatory cytokines and is implicated in several inflammatory diseases, attempts to directly [...]

Context. “Compound 23” (LEO Pharma) is an oral IL-17A protein−protein interaction modulator being developed for psoriasis and other inflammatory diseases . Like most cytokines, the involvement of IL-17A in chronic inflammatory diseases has been well-researched . IL-17A is the key cytokine that mediates psoriasis , and targeting it or its [...]

There were two novel small molecules approved in May 2022: vonoprazan (Voquezna) : a potassium-competitive acid blocker (PCAB) tapinarof (Vtama) : an aryl hydrocarbon receptor (AhR) agonist And one novel large molecule approval: tirzepatide (Mounjaro) : a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 [...]

In 2021 the FDA approved four new drugs for various immunological diseases, including a molecular glue, the first drug approved for AAV in a decade, and a ROCK kinase inhibitor originally investigated for cancer. This article and slide deck explores each in more detail, including but not limited to their: mechanisms of action target rationale [...]

Context. ”Compound 53” (University of Texas Southwestern Medical Center) is a stimulator of interferon (IFN) genes (STING) agonist . STING agonists have been heavily pursued in cancer immunology as increasing data suggests that the efficacy of immunotherapy can be enhanced by proteins such as STING that can induce a strong innate immune [...]

PRN1008 (rilzabrutinib, Sanofi) is an oral, reversible covalent Bruton’s tyrosine kinase (BTK) inhibitor in a Ph. III trial for immune thrombocytopenia. A simultaneously published inhibitor, PRN473, is in development as a topical treatment for atopic dermatitis. Following target discovery in 1993, and subsequent approval of the first [...]

Compound 14f (Kyowa Kirin) is an oral ChemR23 inhibitor with two acidic sites. Nominated by Bryan McKibben , this article describes a scaffold hopping exercise to address the short half-life of previously described chemical matter, and the successful development of in-vivo tool inhibitors to probe ChemR23 biology in animal models of [...]

There were four novel drugs approved by the FDA in January 2022 (2 small molecules, 2 large molecules). The novel January 2022 new drug approvals appear below in this Drug Hunter minireview: See our overview of all 36 of the novel small molecule and large molecule FDA [...]

Velsecorat (AZD7594) is an inhaled, non-steroidal glucocorticoid receptor modulator and antedrug (soft drug) for treatment of asthma and other respiratory conditions that has completed several Ph. II studies . While the paper states that the results support progression into Ph. III studies, a Ph. III study does not appear to have started and [...]

Kinase inhibitors are increasingly being explored for diseases beyond cancer. While SGK1 has been a cancer target, SGK1 has also been implicated in osteoarthritis pathology, and the Sanofi team developed “compound 17a” to interrogate this. The starting point was identified from ligand-based virtual screening, focusing on the DFG-out [...]

Vanin-1 is a biotinidase (nitrilase superfamily) that hydrolyzes pantetheine. Despite the critical role of pantetheine, vanin-1 deficient mice don’t appear to have issues, but may be protected in inflammatory disease settings like IBD. Since human vanin-1 coverage requirements are unknown, the Pfizer vanin-1 program took a “no-regrets” [...]

“Compound 25,” inhibits HPK1 via a rare “P-loop folded” active site conformation. The molecule was nominated by reviewer Julien Lefranc , and structural biologist Yoana Dimitrova shares some insight here: “The ‘folded P-loop’ conformation is considered “extremely unusual” – authors of a 2011 paper looked into this and found it in only 62 out [...]

The Biogen reversible BTK kinase inhibitor, BIIB091, is a highly selective, phase I clinical candidate for multiple sclerosis. Irreversible BTK inhibitors have been explored and developed extensively, primarily in cancer. Reversible molecules have been less common, with the most clinically advanced molecule being fenebrutinib (phase [...]

The Kezar Life Sciences covalent immunoproteasome inhibitor, KZR-616 , licensed from Onyx , targets the LMP7 and LMP2 active sites of the immunoproteasome, and is currently in Ph. II trials for autoimmune disorders (30 mg SC QW for 2 weeks, then 45 mg SC weekly for 14 weeks). More subunit-selective, proteasome-sparing reversible-covalent LMP7 [...]

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 [...]

The Lycera ROR gamma agonist, cintirorgon ( LYC-55716 ), is a first-in-class phase 1b clinical candidate for cancer immunotherapy (in combination with pembrolizumab in NSCLC). ROR gamma antagonists have been extensively pursued and studied for autoimmune conditions, but ROR gamma agonists have also been recently pursued for “pro-inflammatory” [...]

The Bristol Myers Squibb (BMS) HPK1 kinase inhibitor, “compound 24” is an oral tool compound intended for cancer immunotherapy, with >50x selectivity against family members including GLK. The starting point was an IRAK4 kinase inhibitor identified from historical kinome selectivity data. A homology-model based on MST1 was used for [...]

The Celgene/BMS PKCθ kinase inhibitor, CC-90005 , highlighted by Julien Lefranc , is a clinical candidate in Ph. I for psoriasis, with some dosing being conducted in healthy volunteers. The safety profile is impressive given how fraught with selectivity issues previous PKC inhibitors have been. The molecule is >550-fold selective for PKCθ [...]

The Janssen RORgt inhibitor, JNJ-61803534 , is an oral clinical candidate that was well-tolerated in humans up to 200 mg and demonstrated PD. Unfortunately, development was terminated due to findings in a rabbit embryo-fetal study where fetal development was impacted by JNJ-61803534 treatment. The JNJ team shares a lot of useful human data in [...]

The Eternity Bioscience/Shanghai Hengrui RORγ antagonist, SHR168442, is a skin-restricted, topical compound intended to treat psoriasis. As a master regulator of Th17 immune cells which are significantly involved in allergic diseases, both positive and negative oral modulators of RORγt had been hotly pursued, though many have ceased clinical [...]

Idorsia/Actelion CXCR7 GPCR insurmountable antagonist

BMS-986143 is a potent, reversible inhibitor of the Bruton’s tyrosine kinase (BTK), which has been successfully targeted by a number of irreversible drugs for oncology. The safety bar is much higher for inflammatory conditions, however, which led the BMS team to pursue reversible inhibitors. The two defined axial stereocenters of compounds [...]

GLPG1205 is a potent, selective, and orally bioavailable negative allosteric modulator of the GPCR GPR84, a receptor associated with inflammation. Despite possessing both a dioxane ring and an relatively unhindered alkyne, the molecule has low clearance and is highly bioavailable in preclinical species (>100% F). The molecule was taken into a [...]

OP-5244 is a potent (250 pM), orally bioavailable inhibitor of the nucleotidase CD73, in contrast to the previously highlighted IV inhibitor in July . I thought it was remarkable that the ORIC team was able to identify an orally available, low clearance, and permeable compound with phosphonic acid motif and four other hydrogen bond donors [...]

“compound 23” is a selective CRBN-based degrader of the pseudokinase, IRAK3, with in vitro activity in primary human cells. A volcano plot shows remarkable separation between IRAK3 degradation vs. most other proteins, with very little activity against family members IRAK1 and IRAK4. The authors were able to quickly generate this degrader from [...]

PF-06826647 is a TYK2-selective kinase inhibitor which binds to the catalytically active JH1 kinase domain, in contrast to BMS-986165, a TYK2 inhibitor in Ph. III for psoriasis that binds to the JH2 pseudokinase domain. TYK2-selective inhibitors are expected to have anti-inflammatory activity with reduced side effects such as anemia due to [...]

“compound 7f” is an antagonist of the endosomal TLRs 7/8/9, which induce inflammation in response to internalized single-stranded RNA or hypomethylated double-stranded DNA. Potency and selectivity within endosomal TLR’s (3, 7, 8, 9) and against cell-surface TLR’s (1, 2, 4, 5, 6) has been difficult to achieve . Compound 7f has single-digit [...]

“compound 38a” is an inhibitor of ChemR23, a chemokine-receptor-like GPCR with a role in plasmacytoid dendritic cell (pDC) trafficking. The ChemR23 inhibitor was developed with the intention of suppressing the migration of pDCs, which may be useful in certain autoimmune diseases. A key change that dramatically improved bioavailability was [...]

“compound 2” is a heme-displacing IDO1 inhibitor with a similar binding mode to BMS-986205 with a low projected human dose. A bis-amide hit was generated from a mass-spectrometry based binding screen, and optimized through structure-based drug design. An initial benzamide lead was metabolically unstable due to rapid amide hydrolysis, but this [...]

AB680 is a potent (5 pM) and selective inhibitor of CD73, a nucleotidase that metabolizes AMP to immunosuppressive extracellular adenosine. AB680 is intended to be used in combination with checkpoint inhibitor biologics in cancer immunotherapy, and has a PK profile for biweekly (Q2W) IV dosing in humans based on a Ph. I study in healthy volunteers.

GS-9688 (selgantolimod) is a potent and selective TLR8 agonist sparing related receptor TLR7, and is intended to induce better immune responses in chronic hepatitis B. Since systemic activation of TLR8 was undesirable, selgantolimod was designed to have high first-pass hepatic clearance to induce effective antiviral immunity in the liver but [...]

BMS-986251 is an inverse agonist of RORgt, a hot target in inflammation for a significant period. Unfortunately it looks like development hit a wall in this space, and several publications of various company’s RORgt modulators have appeared in the last several months. Chemically, 251 is interesting with 5 stereocenters, none of which look [...]

“Compound 19” is a JAK1/TYK2 dual kinase inhibitor from Pfizer, related to its clinical JAK1/TYK2 dual inhibitor, brepocitinib, in Ph. II for a variety of inflammatory diseases. The cyclopropyl amide group was designed to displace a high energy water molecule. It was probably fortunate for their manufacturing colleagues that brepocitinib was [...]

“PROTAC 6” (GlaxoSmithKline (GSK) IAP-based selective RIPK2 degrader with prolonged in vivo PD)

GSK620 (GlaxoSmithKline (GSK) oral in vivo BD2 domain selective BET inhibitor)

Arcus CD73 inhibitor (Arcus non-nucleoside CD73 inhibitor)

GS-9876 (lanraplenib) (Gilead Sciences oral SYK selective kinase inhibitor clinical candidate)

RORγt inhibitor from Merck (Merck ROR-gamma-t oral in vivo allosteric inhibitor)

BMS-986260 (Bristol Myers Squibb (BMS) oral in vivo selective TGF-beta-R1 kinase inhibitor)

February’s molecule, the Novartis factor B inhibitor LNP023 , targets the serine protease factor B (FB), a key node in the complement system. The complement part of the innate immune system is a hot area for drug discovery due to its increasingly recognized role in a wide range of chronic human diseases, including age-related macular [...]

February’s molecule, the Novartis factor B inhibitor LNP023 , targets the serine protease factor B (FB), a key node in the complement system. The complement part of the innate immune system is a hot area for drug discovery due to its increasingly recognized role in a wide range of chronic human diseases, including age-related macular [...]

While biologic drugs currently dominate in immunology by sales , small molecule immunomodulators (SMIMs) are making a comeback fueled by better understanding of intracellular signaling pathways and new hit finding technologies. SMIMs can be grouped into two categories: those that engage large molecule (LM) targets in a new [...]