The Pharma Digest

Daily drug discovery research and pharma industry news — medicinal chemistry, pharmacology, computational drug discovery.

Archive · 2026 · October 2026

Daily digest — 2026-10-21

2026-10-21

Five science items today: a hERG-cleaned DCN1–UBE2M inhibitor, a DNA-based CENPB degrader, a single-dose malaria candidate now in phase 1, an interpretable P-gp redesign tool and an FGFR3-selectivity perspective. Business is thin: China's draft curbs on foreign biopharma acquisitions.

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Medicinal Chemistry

4 articles

2026-10-19 · ⚗️CENPB / DNA-based PROTAC (OligoTAC) · Journal of Medicinal Chemistry (ACS)

A DNA-based PROTAC degrades CENPB in TKI-resistant lung cancer models

Targeted protein degradationOncology
  • CENPB, the sequence-specific DNA-binding protein at centromeres, is overexpressed in aggressive cancers, yet has no direct inhibitors.
  • CENPB OligoTAC links a CENPB-binding oligodeoxynucleotide to an E3 ligase ligand, driving CENPB ubiquitination and proteasomal degradation, centromere disruption and apoptosis.
  • It was active in NSCLC models resistant to first-, second- and third-generation TKIs, with little toxicity to normal cells, good serum stability and a favorable in vivo PK and tolerability profile.
💡 Points

Using the protein's own DNA recognition sequence as the warhead sidesteps the need for a small-molecule pocket, which is the appeal for transcription-factor-like targets. The open questions I would press on are delivery beyond mouse models, oligonucleotide manufacturing cost, and whether the selectivity for tumor over normal cells holds up when CENPB is expressed everywhere.

Centromere-Targeting Chimeras for Combating Cancer Drug Resistance ↗

2026-10-19 · ⚗️DCN1–UBE2M interaction (neddylation) · Journal of Medicinal Chemistry (ACS)

Dialing hERG out of a DCN1–UBE2M inhibitor without losing potency

SAR & lead optimizationSafety & toxicologyProtein–protein interactions
  • The earlier tool compound NAcM-OPT blocked the DCN1–UBE2M interaction, was orally available and slowed xenograft growth, but carried significant hERG affinity that stalled development.
  • The authors systematically modified the scaffold to cut hERG binding while keeping DCN1 engagement.
  • Lead compound 110 matched the parent in biochemical and cellular potency, with better physicochemical properties and improved selectivity against hERG.
💡 Points

This is the unglamorous but necessary second act: a validated PPI chemotype that was dead on cardiac safety, rescued by SAR alone. The takeaway for anyone with a basic, lipophilic PPI binder is that hERG can often be engineered out without giving up the pharmacophore, so check your own series before abandoning it.

Reducing off-Target hERG Activity of First-Generation DCN1-UBE2M Interaction Inhibitors: Design, Synthesis, and Structure−Activity Relationships ↗

2026-10-19 · ⚗️FGFR3 (selective kinase inhibitors) · Journal of Medicinal Chemistry (ACS)

Perspective: how structure-guided design finally delivered FGFR3-selective inhibitors

SAR & lead optimizationOncologyKinases
  • Second-generation pan-FGFR inhibitors proved the concept but were limited by toxicities from inhibiting FGFR1, FGFR2 and FGFR4.
  • Despite high structural homology across the family, structure-guided work has produced the first FGFR3-selective inhibitors to reach clinical evaluation.
  • The Perspective covers the biological rationale, the design strategies behind the selectivity and emerging indications, including bladder cancer and achondroplasia.
💡 Points

Isoform selectivity inside a highly conserved kinase family is a good test of how far structure-based design really goes, and FGFR3 now has clinical-stage answers. The achondroplasia angle is the interesting one: a chronic, pediatric-adjacent indication raises the tolerability bar far above oncology, which is exactly where selectivity pays off.

FGFR3 Selectivity in Drug Discovery: Biological Rationale, Design Strategies, and Therapeutic Potential ↗

2026-10-19 · ⚗️Plasmodium falciparum (blood stage), pyrazine-2-carboxamide · Journal of Medicinal Chemistry (ACS)

A pyrazine-2-carboxamide antimalarial that cures mice in one dose has entered phase 1

Hit finding & screeningSAR & lead optimizationInfectious disease
  • A P. falciparum growth-inhibition screen identified a new pyrazine-2-carboxamide series for blood-stage malaria.
  • Lead optimization improved anti-plasmodial potency and metabolic stability and reduced CYP2D6 inhibition risk, giving IWY357.
  • A single dose was fully curative in a Pf-humanized SCID mouse model, resistance selection showed a high barrier, and the compound has progressed through GLP toxicology into phase 1.
💡 Points

A phenotypic hit taken all the way to the clinic with a single-dose cure in the humanized-mouse model is what the field has wanted since resistance to front-line agents began eroding. The CYP2D6 fix matters for combinations, which is where a short-course regimen would actually live. I would watch the human PK, since a single-dose claim lives or dies on exposure.

Discovery of a Pyrazine-2-Carboxamide Derivative as a Potent Plasmodium falciparum Inhibitor with Potential for Single-Dose Cure ↗

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Computational & AI

1 article

2026-10-19 · 💻P-gp efflux / computational design · Journal of Chemical Information and Modeling (ACS)

Fragment-synergy genetic algorithm turns P-gp substrates into non-substrates

DMPK & ADME
  • P-gp efflux limits bioavailability and CNS exposure, and ML substrate classifiers rarely translate into concrete design moves.
  • SF-GA builds fragment synergy analysis into the mutation step of a genetic algorithm, biasing replacements toward substructures that co-occur in non-substrates.
  • Against GA and reinforcement-learning baselines at a fixed evaluation budget it was competitive and gave the most synthetically accessible molecules, reporting the removed and inserted fragments for every accepted mutation.
💡 Points

The part I would use is the per-mutation fragment report: it reads like a matched-pair suggestion list, which is how a chemist actually wants a model to talk. Competitive rather than better optimization performance means the value is interpretability and synthesizability, not raw efficiency. Prospective validation on real efflux assays is the missing piece.

Synergy-Guided Molecular Redesign of Predicted P-Glycoprotein Substrates toward Synthetically Feasible Non-Substrates ↗

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Industry News

1 article

2026-10-19 · 🏢Policy / M&A restriction · STAT News · China (regulators) / foreign acquirers of Chinese biotech

China proposes curbs on foreign acquisitions of critical biopharma technologies

Oligonucleotides & RNACell & gene therapyM&AChina biotech
  • China is proposing new restrictions on foreign acquisitions of critical biopharma technologies as it seeks to keep control of its fast-growing drug development industry.
  • Trade coverage of the draft (Fierce) describes it as targeting full transfers of proprietary cell and gene therapy, siRNA and pathogen gain-of-function platforms, while standard out-licensing and CRO/CDMO outsourcing appear to be exempt.
  • The final text and timing are not confirmed.
💡 Points

If licensing really stays exempt, the draft mostly shuts the door on buying a Chinese platform company outright while leaving the license-in model that Western pharma has leaned on intact. That nudges deal structure toward options and NewCo licensing, not away from China. Buyers of cell, gene and siRNA platforms are the ones who should re-run their pipelines of targets.

STAT+: China moves to restrict foreign biotech acquisitions ↗