July’s Molecules of the Month include Novartis’ molecular glue degrader which induces fetal hemoglobin for sickle cell disease and Pfizer’s tinlorafenib, a brain-penetrant BRAF V600E-mutant inhibitor for melanoma with brain metastasis. We also feature AZ-PRMT5i-1, an MTA-cooperative PRMT5 inhibitor for MTAP-deficient cancers from AstraZeneca. Other notable molecules from July include MTX-531, a dual EGFR/PI3K inhibitor, and XC219, a CDK-targeting molecule from LifeMine Therapeutics discovered through a top-down drug discovery approach. Additionally, paxalisib continues to advance in the clinic with encouraging new data for glioblastoma, while an OX2R-selective agonist from Takeda offers potential in Alzheimer’s disease.
You can read more about the compounds that made our July 2024 Molecules of the Month list and check out recent articles for each, linked below:
dWIZ-2 – A novel molecular glue degrader that targets the WIZ (widely interspaced zinc finger motifs) transcription factor to induce HbF (fetal hemoglobin) production, offering a potential therapeutic strategy for SCD (sickle cell disease). Identified through phenotypic screening of a cereblon-biased chemical library, WIZ was revealed as a previously unknown repressor of HbF. The pharmacological degradation of WIZ, mediated by dWIZ-2, was well tolerated and effectively induced HbF in humanized mice and cynomolgus monkeys. Interestingly, Novartis appears to have progressed a WIZ degrader to Ph. I/II clinical trials (NCT06546670), however, the structure and target of ITU512 remains undisclosed. You can learn more about Novartis’ molecular glue WIZ degraders in our May 2024 patent highlights.
tinlorafenib (PF-07284890, ARRY-461) – A brain-penetrant BRAF V600E-mutant inhibitor from Pfizer’s Boulder site developed to address the challenge of treating melanoma which has metastasized to the CNS, a limitation of first-generation BRAF V600E inhibitors. PF-07284890 was discovered through SBDD and optimization of physicochemical properties, including lowering molecular weight, TPSA, and reducing hydrogen bond donors to bypass efflux transporters. In preclinical studies, it demonstrated robust tumor regressions in both peripheral and intracranial BRAF V600E melanoma models. Based on these promising results, PF-07284890 advanced to a Ph. I clinical trial (NCT04543188) for patients with BRAF V600E-mutant solid tumors, including those with brain metastases, but the program was terminated last year during a pipeline refocusing effort.
compound 16 – Cerevel’s GFRα (glial cell line-derived neurotrophic factor family receptor alpha) 2/3-selective small molecule inhibitor which avoids inhibition of RET (rearranged during transfection) receptor tyrosine kinase, was identified through a 70 billion compound DEL screen and subsequent SAR optimization. While initially identified as a dual GFRα2/3 inhibitor (compound 3), further refinement led to compound 16, which, despite reduced selectivity over GFRα1, demonstrated increased potency towards GFRα2/3. Although the authors acknowledge the limitations in the compound's physicochemical properties, this work is notable for developing GFRα2/3 inhibitors that could disrupt the ligand-RET-GFRα complex, offering a potential therapeutic strategy for treating pain and itch.
AZ-PRMT5i-1 – AstraZeneca’s orally bioavailable MTA-cooperative PRMT5 inhibitor developed for treating MTAP-deficient cancers. Identified through high-throughput biochemical screening and optimized via SBDD, AZ-PRMT5i-1 features key modifications, including bioisosteric replacement of the thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold, and targeted substitutions in the azaindole headgroup. These changes improved potency, MTA cooperativity, and drug-like properties. AZ-PRMT5i-1 demonstrates single-digit nM potency, >50-fold MTA cooperativity, and favorable DMPK properties, showing significant in vivo efficacy in several MTAP-deficient cancer models. You can learn more about AstraZeneca’s spirocyclic selective MTA-cooperative PRMT5 inhibitor program from our February 2024 patent highlights.
MTX-531 – A computationally designed dual EGFR (epidermal growth factor receptor) and PI3K (phosphatidylinositol 3-OH kinase) inhibitor that targets key resistance drivers in cancer, with low-nanomolar potency and high specificity. It demonstrated significant efficacy in squamous head and neck PDX models as a monotherapy, leading to tumor regressions. Additionally, when combined with KRAS G12C-mutant inhibitors, MTX-531 produced durable regressions in BRAF-mutant or KRAS-mutant colorectal cancer PDX models, significantly extending median survival. MTX-531 is well tolerated in mice and, unlike typical PI3K inhibitors, does not induce hyperglycemia. This is likely due to its weak agonist activity on peroxisome proliferator-activated receptor-γ, which provides a favorable therapeutic index.
XC219 – A lysine-targeting kinase inhibitor developed through a novel top-down drug discovery approach from LifeMine Therapeutics, which began with a large-scale digital search of over 100,000 fully sequenced fungal genomes to identify molecules targeting specific human proteins. Initially, two compounds were discovered that inhibit therapeutically important CDKs (cyclin-dependent kinases) by forming a site-selective covalent bond with the CDK active site lysine. Through SAR exploration, XC219 was identified with improved kinase selectivity, bioavailability, and efficacy. This work demonstrates the potential of top-down drug discovery to uncover mechanistically and structurally novel molecules for drug development.
paxalisib (GDC-0084) – A brain-penetrant PI3K (phosphoinositide 3-kinase) inhibitor, originally discovered by Genentech, has shown promising results in Ph. II trials for treating DIPG (diffuse intrinsic pontine glioma) and other DMGs (diffuse midline gliomas). Kazia Therapeutics, which licensed paxalisib from Genentech, is advancing its development for newly diagnosed glioblastoma and other brain cancers. Paxalisib has been involved in ten clinical trials, including a completed Ph. II study in glioblastoma, with further data expected from the pivotal GBM AGILE study later in 2024 (NCT03522298). The drug has received multiple FDA designations, including Orphan Drug and Fast Track for glioblastoma, DIPG, and other brain tumors, as well as Rare Pediatric Disease designation for DIPG.
compound 42 – A non-nucleoside oxazolidinone inhibitor of herpesvirus DNA polymerase from Merck demonstrating potent broad-spectrum activity against multiple herpesviruses, including CMV, VZV, HSV1/2, EBV, and HHV6. In murine models, compound 42 was efficacious against both HSV-1 and CMV infections. This compound represents a promising candidate for addressing the limitations of current nucleoside treatments such as poor tolerability, resistance, and a narrow spectrum of activity, particularly in immunocompromised patients. Notable, the SAR optimization was facilitated by a nickel-mediated aryl-alkyl photochemical coupling method developed by the MacMillan group. This approach allowed the oxazolidinone stereocenter to be set early in the analog synthesis, eliminating the need for a late-stage chiral separation.
enzomenib (DSP-5336) – Sumitomo’s clinical small molecule inhibitor targeting the interaction between menin and MLL (mixed-lineage leukemia) proteins. In preclinical studies, DSP-5336 demonstrated selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations. It reduced the expression of leukemia-associated genes (HOXA9 and MEIS1) and increased the expression of the differentiation gene CD11b. DSP-5336 is currently in a Ph. I/II clinical trial for patients with relapsed or refractory acute leukemia (NCT04988555). The FDA has granted it Orphan Drug designation for AML (acute myeloid leukemia) and Fast Track designation for relapsed or refractory AML with MLL rearrangements or NPM1 mutations.
OX-201 – An orally bioavailable OX2R (orexin receptor 2)-selective agonist from Takeda that increases neuronal activity and promotes tau release into the hippocampal ISF (interstitial fluid) without exacerbating tau accumulation, even in a tauopathy model (P301S tau Tg mice). Given that tau release is activity-dependent and typically occurs during wakefulness, OX-201’s ability to enhance wakefulness while maintaining tau efflux suggests that such agonists could support the lymphatic clearance of pathological proteins by optimizing daytime arousal and improving nighttime sleep. Despite the differences between P301S tau Tg mice and individuals with AD (Alzheimer's disease) in sleep/wake patterns, these findings indicate that OX-201 may offer therapeutic potential for AD without increasing tau burden in the hippocampus, even under conditions of hyperarousal.
Reviewer Commentary from Callie Bryan
The 'top-down drug discovery' approach taken by Verdine and coauthors [LifeMine Therapeutics] is a novel way to find chemical matter for a notoriously difficult-to-gain-selectivity-for target, i.e., CDK2. In so doing, they identified a very novel covalent CDK2i that modifies a Lys in the active site via a vinylogous anhydride. Nothing about the molecule follows a standard kinase inhibitor model, and I remain skeptical about the selectivity given the problems associated with inhibiting closely related family members (see Figure 9A), but the strategy remains interesting.
“Paxalisib was developed to get through the BBB particularly because cancers such as glioblastoma are so deadly, still characterized by poor prognosis and limited treatment options. That it gained Orphan Drug status and continues to show positive results in the clinic is a testament to the dedication of the team that made it who were driven both personally and professionally to find cures to glioblastoma, and to Kazia that continues to push it forward.
Reviewer Commentary from Christian Kuttruff
Historically, natural product-based drug discovery has led to significant pharmaceutical breakthroughs, including chemotherapeutic agents, statins, and antibiotics. However, this approach has encountered challenges, such as the frequent rediscovery of known molecules, limited novel screening methods, and difficulties in analoguing and producing natural products.
“Recent advancements in genome mining and identifying self-resistance genes within biosynthetic gene clusters have sparked a paradigm shift in natural product drug discovery. The LifeMine Tx paper is particularly noteworthy in this context, as it represents, to my knowledge, the first comprehensive demonstration of this technology's potential to deliver natural product-based hits for predetermined human targets. Notably, before the LifeMine Tx paper, there was a 2022 preprint publication in BioRxiv from Zymergen (before being acquired by Ginkgo) but the paper never appeared in a peer-reviewed journal to the best of my knowledge and they did not further optimize their hits.
“The paper's value is further amplified by its elucidation of the covalent mechanism of the hits, exploration of the structure-activity relationship through semi and total synthesis, and the successful development of a potent CDK2 inhibitor demonstrating efficacy in a xenograft model. I am personally looking forward to seeing the first clinical compounds emerge from this exciting approach.
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