Kerry Betz

BLU-222 is a potential first-in-class, orally bioavailable selective inhibitor of CDK2 discovered and currently in development by Blueprint Medicines for the treatment of advanced solid tumors. Read the full case study to learn about the competitive landscape of CDK inhibitors, the discovery story enabled by the DiscoveRx KINOMEscan screening platform, how exquisite kinome selectivity can be achieved despite ~100% active site sequence similarity between CDK1/2, how this molecule can potentially treat CCNE1-amplified and CDK4/6i-resistant tumor models, interim clinical data, and more.

ORIC-533, a potential best-in-class oral inhibitor of CD73 from ORIC Pharmaceuticals, is currently in a Ph. Ib trial for relapsed/refractory multiple myeloma (MM). It inhibits the CD73-mediated conversion of AMP to adenosine which generates an immunosuppressive tumor microenvironment and has the potential to be a next-generation immunotherapy. The in-depth use of X-ray structures led the team to discover a novel set of phosphonate bioisosteres which acheived bioavailability in a polar scaffold. The structure and discovery of ORIC-533 were recently disclosed at the ACS Spring 2024 Meeting.

Vertex’s VX-548 is a potential first-in-class, exquisitely selective, oral NaV1.8 inhibitor that recently captured headlines for its positive Ph. III data. With the ongoing opioid epidemic throughout the US, there is an urgent unmet medical need for non-addictive pain medications as alternatives to opioids. They plan to file an NDA by mid-2024 for the treatment of moderate-to-severe acute pain. This case study highlights what’s publicly known about Vertex’s journey in pain leading up to the Ph. III readout for VX-548, and why this is such a watershed moment for pain management.

PF-9363 (CTx-648) is a first-in-class, oral inhibitor of the KAT6A/B histone lysine acetyltransferases (HATs) for the treatment of ER+/luminal & KAT6A+ breast cancer discovered by Melbourne’s Cancer Therapeutics CRC (CTxT) and Pfizer, San Diego. This article discusses why the molecule is scientifically notable in drug discovery for epigenetic targets and transferable scientific insights from its decade-long KAT6 campaign including its target rationale, hit-finding and lead optimization, synthesis and relevant clinical data.

LUNA18 is an orally bioavailable, cell-penetrant, macrocyclic peptide pan-RAS inhibitor (Chugai ’21Q3 earnings call) intended for the treatment of KRAS-mutant cancers. It disrupts the protein-protein interaction between KRAS and SOS, preventing RAS activation.

AZD4747 is a CNS-penetrant, oral KRAS G12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibitors have tended to be quite large and fall outside the range of physicochemical properties generally required for CNS permeability. (MW < 360 Da, cLogD < 2, TPSA < 90 Å2. AZD4747 is much smaller than marketed KRAS G12C inhibitors but maintains exceptional cellular potency. The team also encountered an unexpected toxicity that scientists working on covalents should pay attention to.