GS-6207 is an HIV-1 inhibitor that acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is [...]

A-1331852 is a highly potent, orally bioavailable inhibitor of BCL-XL, blocking a protein-protein interaction resulting in tumor cell apoptosis. The compound was an important tool compound for understanding the biology of BCL-family protein inhibitors (particularly around heme toxicities), and ultimately led to the development of an [...]

“Compound 6f” is a potent macrocyclic factor XIa inhibitor (<1 nM) that is highly selective against other serine proteases and has excellent oral PK (high bioavailability, low clearance). The BMS team was able to troubleshoot metabolic instability through met. ID, which revealed a hotspot outside of the macrocycle.

DS-1971a is a potent, isoform-selective selective arylsulfonamide NaV1.7 inhibitor intended for the treatment of neuropathic pain. It has a surprisingly long residence time on NaV1.7, which the authors suggest contributes to better than predicted in vivo activity. 1971a is a good example of a compound which was successfully advanced to [...]

April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849 , has been a hotly followed compound in development as it is the closest clinical KRAS inhibitor to the likely soon-to-be approved AMG-510 (sotorasib). The KRAS clinical race easily would have been the most followed development story of 2020 had it not been for COVID, due to the [...]

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

January’s molecule, a Novartis FXR partial agonist (LMB763 (nidufexor)), modulates the farnesoid X nuclear receptor (FXR), a hot target for NASH due to promising prior clinical activity with bile acid-derived FXR agonists such as OCA. OCA, however, showed significant rates of side effects including itching (likely due to GPBAR1 bile acid receptor agonism) and elevated LDL cholesterol levels, which is problematic for the more heart-disease-susceptible NASH patient population. [...]

A Ph. II liver-targeting HBV core protein modulator optimized for ADMET properties. Linvencorvir (RG7907), a novel HBV core protein allosteric modulator, offers a promising treatment option for chronic hepatitis B which affects 296 million people globally. It possesses an interesting glue-like mechanism that causes the HBV core protein to [...]

Kyowa Kirin’s KW-6356, or sipagladenant , is a non-xanthine A 2A receptor intended to treat Parkinson’s disease. Unlike Kyowa Kirin’s recently US-approved neutral antagonist, istradefylline, the molecule is an [...]

Here’s a common scenario - your team has just completed a phenotypic screening campaign, cleaned out the false positives through hit triage , and now you have modestly optimized validated leads with cell-based activity. The problem is, you have no idea how your compounds work, and whether they act on a target or set of targets that are worth [...]

An oral, potentially CNS-penetrant BTK inhibitor for multiple sclerosis, a reversible pan-KRAS inhibitor, and a squaramide-containing clinical candidate are just some of the examples for this month's MOTM.  Stay tuned for the full case studies which will cover why the molecules matter, how they were discovered, the key steps behind optimization, how they work, why the targets were chosen, any interesting toxicology and clinical data, and more.  In the meantime, you can find recent news and articles that inspired us to write up these stories below: fenebrutinib - An oral BTK inhibitor that rec...

Tumors can evade the immune system through the recruitment of regulatory T cells (Treg) which limit the activation and expansion of effector T cells (Teff). IKZF2 (Helios) is an Ikaros transcription factor family member that is expressed in a majority of Treg cells [...]

Recently disclosed in Nature , Janssen’s JNJ-1802 is the first dengue virus NS3-NS4B protein-protein interaction inhibitor to enter the clinic. The molecule is derived from a related chemical series to JNJ-A07 , which was also disclosed in Nature in 2021 and highlighted as a Molecule of [...]

Acute myeloid leukemia (AML) remains difficult to treat, with few novel therapies approved in the last three decades. A subset of these aggressive leukemias, mixed lineage leukemias , are driven by fusions between the MLL1 gene (“Mixed Lineage Leukemia”, or KMT2A) and more than 80 [...]

Pfizer has announced the FDA-approval of zavegepant ( ZAVZPRET TM , BHV-3500) for the treatment of acute migraine in adults based on positive Ph. II/III results. As the first and only calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray [...]

A significant section of the Inflation Reduction Act (H.R. 5376) recently signed into law was targeted at lowering public spending on prescription drugs (Subtitle B: Prescription Drug Pricing Reform). The new laws include Medicare negotiation and includes a provision that disproportionately affects small molecules which have triggered [...]

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 [...]

There were plenty of scientific highlights from the literature that we didn’t have space for in Molecules of the Month - here’s a reader’s digest rounding up ~20 molecules of potential interest that we didn’t have space to highlight, including Pfizer’s covalent heterobifunctional BTK degrader, BMS' brain-penetrant GSK-3β inhibitor, the [...]