Seven science items: a fumarate-handle TTK degrader, electrophile-first UBE2D2 inhibitors, a selective macrocyclic CDK7 series, PDE4B and MKK3 programs, inhaled DDR inhibitors, and a cofolding benchmark. Business: Roche–Hansoh ADCs, GSK's hepatitis B approval, Roivant's uveitis data.
2026-10-20 · ⚗️DDR1/DDR2 / inhaled small molecule · Journal of Medicinal Chemistry (ACS)
Respiratory & fibrosis
- Structure-based design delivered two 5:6 heterocyclic series with strong DDR1/DDR2 affinity and a promising kinome selectivity profile.
- An inhaled-by-design strategy then tuned potency, physicochemical and in vitro ADME properties toward lung-restricted compounds.
- Compound 25 combined antifibrotic activity in a TGF-β-induced in vitro fibrosis model with a favorable pharmacokinetic profile for local delivery.
💡 PointsInhaled kinase inhibitors live or die on lung retention versus systemic clearance, and designing for that from the start is the right call rather than retrofitting a systemic compound. The pitfalls I'd watch are lysosomal trapping and mucociliary clearance, which in vitro ADME rarely captures. DDR biology is compelling in fibrosis, but it's still a target waiting for clinical validation.
Lung-Tailored Pyrrolo-pyrimidine DDR Inhibitors Designed for Optimized Local Delivery ↗
2026-10-20 · ⚗️CDK7 / macrocyclic kinase inhibitor · Journal of Medicinal Chemistry (ACS)
- Structure-based optimization of a 17-membered macrocyclic pyrazolo-triazine scaffold gave a potent CDK7 inhibitor.
- It showed no significant off-target activity across a panel of more than 400 kinases, addressing the poor selectivity of earlier CDK7 inhibitors.
- In cells it caused cell-cycle arrest, suppressed transcription and lowered c-Myc, especially in triple-negative breast cancer lines, with oral bioavailability and linear PK.
💡 PointsA clean result across 400+ kinases is rare for CDK7, where the covalent field has leaned on THZ-type warheads. A non-covalent macrocycle that is also orally exposed is the profile I'd actually want to pick up for a transcriptional-addiction indication. The open question is on-target toxicity, since selectivity among kinases won't spare you CDK7's role in normal transcription.
Discovery of Pyrazolo[1,5-a]-1,3,5-Triazine Derivatives as Potent, Highly Selective and Orally Available Macrocyclic CDK7 Inhibitors ↗
2026-10-20 · ⚗️MKK3 / non-ATP-competitive modulator · Journal of Medicinal Chemistry (ACS)
- ATP-competitive p38 inhibitors failed in the clinic partly through poor kinome selectivity, so the authors targeted the upstream kinase MKK3 through a non-ATP-competitive pocket.
- The lead, (R)-48, suppressed TNF-α production, was highly orally bioavailable and showed dose-dependent efficacy with clear PK/PD relationships in mouse ulcerative colitis models.
- Biophysical data (HDX-MS) were used to probe how the compounds engage MKK3.
💡 PointsMoving one node upstream of p38 is a sensible way around the selectivity problem that sank the first-generation inhibitors. An oral, TNF-lowering small molecule for UC would be a genuinely different option next to injectable biologics. My concern is the allosteric pocket: SAR for non-ATP-site kinase binders can be steep and hard to translate between species, so I'd check the human-protein data early.
Design and Synthesis of Novel, Non-ATP-Competitive MKK3 Modulators as Suppressors of TNF-α Production for the Treatment of Ulcerative Colitis ↗
2026-10-20 · ⚗️TTK / monovalent degrader (RNF126) · Journal of Medicinal Chemistry (ACS)
- Appending an electrophilic monomethyl fumarate handle to a TTK inhibitor gave a single-warhead degrader, with no E3 ligand attached.
- The lead compound drove TTK degradation and showed stronger antiproliferative activity than the parent inhibitor across several cancer cell lines.
- Mechanistic work points to the E3 ligase RNF126, which the compound stabilizes in complex with TTK, leading to ubiquitination and proteasomal turnover.
💡 PointsMonovalent degraders are attractive because you keep the molecular weight and permeability of a plain inhibitor. The catch is that a fumarate handle is a cysteine-reactive group, so I'd want proteome-wide reactivity data before believing RNF126 is the whole story. Still, if the handle transfers across kinase scaffolds, it's a cheap trick to try on any inhibitor series you already own.
Discovery of Threonine Tyrosine Kinase (TTK) Degraders Utilizing an Electrophilic Monomethyl Fumarate Handle ↗
2026-10-20 · ⚗️UBE2D2 (E2 ubiquitin-conjugating enzyme) / covalent inhibitor · Journal of Medicinal Chemistry (ACS)
- An electrophile-first screen, combined with X-ray crystallography, found a covalent hit that engages two cysteines (C85 and C111) of UBE2D2.
- Structure-guided SAR on the amide and ester groups removed binding to C111 while improving engagement of C85.
- The optimized analog inhibited UBE2D2 activity in vitro and suppressed proliferation of A549 lung cancer cells.
💡 PointsE2s have long been written off as undruggable, so seeing a crystal-supported covalent series is a real step. The interesting design move is dialing out the second cysteine, which is exactly what you need before calling anything a probe. I'd now ask how it behaves across other UBE2D family members, since the active-site cysteine is conserved and selectivity will be the hard part.
Electrophile-First Screening Identifies Covalent Aminothiazole Scaffold Inhibitors for Ubiquitin-Conjugating Enzyme UBE2D2 ↗
2026-10-20 · ⚗️PDE4B / small-molecule inhibitor · Journal of Medicinal Chemistry (ACS)
- The authors set out to improve on the only approved PDE4B-preferential drug, nerandomilast, which is only about 9-fold selective over PDE4D.
- YKS-34 is a potent PDE4B inhibitor with more than 1000-fold selectivity over PDE4A, PDE4C and PDE4D.
- It suppressed TGF-β-driven fibroblast activation and LPS-induced TNF-α release in vitro, and showed favorable PK with accumulation in lung tissue.
💡 PointsPDE4D inhibition is what drives nausea and vomiting, so going from 9-fold to over 1000-fold is the right kind of optimization to chase. The pocket differences between B and D are tiny, which makes me curious what the binding mode looks like. I'd want to see this in a bleomycin model with a therapeutic dosing regimen before getting too excited.
Discovery of YKS-34, a Highly Selective PDE4B Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis ↗
2026-10-21 · 🏢Regulatory approval · STAT News · GSK
- STAT reports that GSK has won FDA approval for its hepatitis B drug.
- The drug extended functional cures to far more patients than previous methods, according to the report.
- Details beyond the headline were not available to us; the product is understood to be the antisense bepirovirsen.
💡 PointsA functional-cure label in hepatitis B is a landmark for the field, and GSK gets it with an antisense oligo, not a small molecule or antibody. The commercial question is uptake: finite treatment courses mean less recurring revenue per patient, but a large, long-diagnosed population. Watch Vir, Arbutus and the Chinese siRNA players, who now have a bar to clear.
STAT+: GSK picks up hep B drug approval ↗
2026-10-21 · 🏢Trial result · STAT News · Roivant
- STAT reports that Roivant announced positive trial results for its immune drug in non-infectious uveitis.
- The result could open a new market for the drug beyond its current indications.
- Only the headline and lede were available to us; the specific endpoints and data are not confirmed here.
💡 PointsUveitis is a small but sticky indication where a non-steroid oral option is valued, and another label extension spreads development cost across more indications. The market will want to see the effect size against the standard of care, not just the win itself. I'd expect this to feed straight into Roivant's partnering and financing narrative for the asset.
STAT+: Roivant says closely watched immune drug succeeded in new eye disease ↗
2026-10-19 · 🏢Collaboration / license (ADC) · Fierce Biotech · Roche / Hansoh Pharma
- Roche and China's Hansoh signed a collaboration on a portfolio of early-stage antibody-drug conjugates, its second ADC deal after a 2025 CDH17 ADC license.
- Reports put the upfront at about $400 million plus a further $110 million after a year, with total potential payments above $15 billion and royalties.
- Hansoh leads early development through global phase 1a, after which Roche takes over development outside Greater China.
💡 PointsThe structure is the story: a platform-style deal where the licensor runs the work through phase 1a looks like Roche buying options on China's early ADC output rather than a single asset. A headline above $15 billion is mostly back-end milestones, so the real signal is a near-$500 million near-term cash commitment. It also keeps Roche in the race with Merck, Pfizer and AstraZeneca for Chinese ADC supply.
Licensing galore: Roche ties up with Hansoh on ADCs as Rani rounds out week with Chugai pact ↗