Four science items today: a single-atom switch that flips NSD2/GSPT1 degrader selectivity, light-activated VEGFR2 inhibitors for the eye, FTO inhibitors for AML and pan-YTHDF m6A reader ligands. Business covers CSL–Alentis, Shionogi's IntraBio buyout, Genmab's Rina-S data and Jaypirca's first-line CLL approval.
2026-10-05 · ⚗️YTHDF1/2/3 m6A reader ligands · chemRxiv
- YTHDF1, YTHDF2 and YTHDF3 read m6A-modified mRNA in the cytosol, and this preprint reports a protein structure-based medicinal chemistry campaign against them.
- The aim is ligands that bind all three paralogs, rather than one reader at a time.
- Only the abstract opening was accessible, so potency and cellular data are not covered here.
💡 PointsThe YTH domains' aromatic cage is a tough, charged pocket, so any structure-guided progress on it is worth tracking. A pan-paralog ligand is a sensible choice, given the redundancy among the three readers. I'd want selectivity over YTHDC1/2 and evidence of cellular target engagement before calling this a probe.
Structure-Based Design of Potent Pan-YTHDF Ligands ↗
2026-10-04 · ⚗️FTO (m6A demethylase) inhibitors · Journal of Medicinal Chemistry (ACS)
- A 67-compound SAR campaign on pyridazine-containing nicotinamides gave E6 as the most active FTO inhibitor, with binding confirmed by MST, CETSA and DARTS.
- E6 was active against MOLM-13 cells, raised global m6A, upregulated ASB2 and RARA and lowered c-Myc.
- It showed acceptable CYP safety and PK and inhibited MOLM-13 xenograft growth.
💡 PointsAnother FTO series, but the useful part is the new scaffold: FTO chemotypes are still thin, and most earlier ones lean on the same few motifs. Potency is modest, so I'd treat E6 as a starting point and look for selectivity over ALKBH5 and other AlkB family members before reading too much into the cell phenotype.
Discovery of Novel Pyridazine-Containing Nicotinamide Derivatives as Potent FTO Inhibitors for Acute Myeloid Leukemia ↗
2026-10-04 · ⚗️NSD2 / GSPT1 degraders (CRBN) · Journal of Medicinal Chemistry (ACS)
- Starting from LLC0424, an NSD2 degrader that also engages GSPT1, a single-atom change gave two close analogues: 424-ND (NSD2-selective) and 424-GD (GSPT1-selective).
- 424-ND suppressed androgen receptor signaling in prostate cancer cells, while 424-GD triggered the integrated stress response.
- Biolayer interferometry showed distinct ternary-complex cooperativity for each target, and simulations suggested different low-energy conformations explain the bias.
💡 PointsDegrader selectivity here tracks ternary-complex cooperativity, not binary affinity, which is exactly what I'd want to see in an SAR table. A matched pair this tight is a ready-made probe set for NSD2 and GSPT1. I'd check proteome-wide selectivity and whether the cooperativity trend holds in cells.
Single-Atom Modification Enables Reversal of Degradation Selectivity between NSD2 and GSPT1 ↗
2026-10-04 · ⚗️VEGFR2 photoactivatable kinase inhibitors · Journal of Medicinal Chemistry (ACS)
- Azido-functionalized VEGFR2 inhibitors EYE1090 and EYE1118 bind the receptor in a light-triggered way while staying potent in the dark.
- Green light that reaches the human retina, including in older eyes, boosted their anti-angiogenic activity in vitro.
- Given orally, both suppressed VEGF-induced retinal leakage in rats and shrank lesions in a mouse choroidal neovascularization model without acute liver toxicity.
💡 PointsAn azide as the photo-switch is a neat, small-footprint handle on a classic kinase scaffold. The appeal is spatial selectivity: systemic exposure with activity concentrated where light focuses. I'd probe how much dark activity remains, which matters for off-target VEGFR2 effects elsewhere, and the photoproduct's fate.
Three Nitrogen Atoms Turn Old Kinase Inhibitors Into New Targetable Remedy ↗
2026-10-05 · 🏢Co-development partnership · Fierce Biotech · CSL / Alentis Therapeutics
- CSL will pay $355 million upfront, plus up to $1.2 billion in commercial milestones, to co-develop and co-commercialize the anti-Claudin-1 antibody lixudebart.
- Profits split 55% CSL and 45% Alentis; CSL funds the ongoing phase 2 in ANCA-associated vasculitis with rapidly progressive glomerulonephritis and a phase 3.
- Phase 2 studies in focal segmental glomerulosclerosis and primary sclerosing cholangitis are also planned.
💡 PointsA 55/45 profit split with a $355M upfront is unusually rich for a phase 2 asset, and it tells me CSL wants a nephrology franchise on real terms. Alentis keeps a meaningful economic stake instead of a royalty. The multi-indication plan across kidney and liver is the bet: one Claudin-1 mechanism, several fibrotic diseases.
CSL pays $355M to co-develop Alentis' phase 2-stage fibrosis drug ↗
2026-10-05 · 🏢Trial result · Fierce Biotech · Genmab / AbbVie
- Genmab reported phase 2 RAINFOL-01 data for the ADC rinatabart sesutecan (Rina-S): a 45.9% confirmed response rate in 109 heavily pretreated patients.
- Median progression-free survival was 9.5 months; TD Cowen analysts called that clearly better than the 5.6 months cited for AbbVie's Elahere.
- Activity was reported regardless of prior Elahere treatment and in patients with low or no FRα expression.
💡 PointsCross-trial comparisons flatter whoever runs the later study, so I'd discount the 'clearly superior' framing. Still, activity in low-FRα and post-Elahere patients is the more interesting claim: it widens the addressable population beyond Elahere's high-expressor label. It also supports the case for the ProfoundBio buy.
Genmab's latest phase 2 data spur claim ADC is 'clearly superior' to AbbVie's Elahere ↗
2026-10-05 · 🏢Regulatory approval · STAT News · Eli Lilly
- The FDA approved Jaypirca (pirtobrutinib) for previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma.
- It moves the non-covalent BTK inhibitor from later-line use into the first-line setting.
💡 PointsFirst-line is where the BTK market's volume sits, so this is the label that matters commercially. It puts a non-covalent inhibitor directly against the covalent incumbents, where it competes on tolerability and on not depending on the Cys481 bond. Watch how payers and guidelines place it relative to fixed-duration venetoclax regimens.
Lilly's Jaypirca approved as first-line CLL therapy ↗
2026-10-05 · 🏢Acquisition · Endpoints News · Shionogi / IntraBio
- Shionogi will acquire Austin-based IntraBio for $2 billion in cash, making it a subsidiary of its US arm.
- The prize is Aqneursa, an oral therapy approved for Niemann-Pick disease type C and, since, for ataxia-telangiectasia.
- Closing is expected in November–December 2026.
💡 PointsBuying a commercial-stage asset outright is a shift for Shionogi, which has leaned on its anti-infective franchise and partnerships. A rare neurology product with two indications adds revenue with a modest sales force and a clear niche. The question is whether Aqneursa can grow past NPC and A-T.
Shionogi to pay $2B for IntraBio, a commercial rare disease biotech ↗