Drugging Kinases

​Inhibitors of protein kinases are now a well-established class of drugs, especially in oncology. Despite high response rates in kinase-addicted tumors, resistance to monotherapy inevitably arises. We are currently developing innovative approaches that target kinases in a way that makes resistance less likely to occur. Our arsenal includes covalent inhibitors, allosteric inhibitors, and small molecule degraders.

​Some example projects include:

  • Development of the first covalent CDK7 inhibitors (the THZ1 series) that achieve selectivity by targeting an unusual cysteine located outside of the kinase domain. Optimized compound (SY-1365) is currently in clinical trials.
  • Development of the first T790M ‘mutant-selective’ inhibitor of EGFR, WZ-4002, which inspired development of Osimertinib by AstraZenenca.
  • Development of the first allosteric inhibitors of Bcr-Abl (GNF-2 and GNF-5) that target the myristate binding site. Optimized version of these compounds, ABL001, is currently in clinical trials.
  • Development of the first potent inhibitor of chromosomal rearrangement oncoproteins NPM-ALK and EML4-ALK, TAE684, which inspired the development of Ceritinib by Novartis.

↑ Back To Top

Targetting Protein Degradation

Heterobifunctional small molecule degraders are an innovative chemical approach, whereby rather than inhibiting protein function, proteins are selectively targeted for degradation by the proteasome. We are synthesizing small molecule degraders that hijack various E3 ligases such as cereblon (CRBN) and VHL, and developing systematic approaches to evaluate effects of degrader molecules. We are also developing cutting-edge technology platforms that enable targeted degradation of any protein of interest.

Our recent accomplishments include:

  • dTAG system. We recently described the dTAG system, a powerful tag-based approach to evaluate the functional consequences of rapid and selective degradation of any single protein in cell-based assays and mouse models . dTAG system uses dTAG molecules, selective FKBP12F36V-fusion degraders with one warhead targeting FKBP12F36V (ortho-AP1867) and the other CRBN (thalidomide), in combination with expression of FKBP12F36V-tagged protein chimeras.
  • CDK9 degrader. By conjugating the CRBN-binding imide with a CDK-binding ligand, SNS-032, we produced a selective CDK9 degrader (THAL-SNS-032) that induces prolonged cytotoxic effects, with distinct advantages over pharmacologic inhibition.
  • Trim24 degrader. By conjugating the VHL-binding ligand VL-269 to a TRIM24 inhibitor, IACS-9571, we developed a selective TRIM24 degrader (dTRIM24) that induces rapid and potent degradation of TRIM24 and identifies TRIM24 as a novel leukemia dependency.
  • ALK degrader. By conjugating a CRBN-binding imide to ALK inhibitors, TAE684 or LDK378, we created two ALK degraders (TL13-12 and TL13-11) that potently degrade ALK in ALK-positive disease models.
  • Kinase degraders. By conjugating the CRBN-binding imide to TAE684, we generated a multi-kinase degrader (TL12-186) that identifies readily degradable kinases such as FLT3 and BTK, leading to the development of FLT3-specific degraders (TL13-117 and TL13-149) and a BTK-specific degrader (DD-04-015).

↑ Back To Top

Drugging Transcription

Cancer cells alter gene transcription programs to drive expression of key survival factor genes that increase their cellular fitness. These aberrant transcription states often arise from misregulation of key master transcription factors, as well as critical transcription cofactors with catalytic activity that these oncogenic gene expression programs are uniquely dependent upon.Using a combination of pharmacological and chemical genetics tools we have identified transcription cyclin-dependent kinases (CDKs) 7, 12, 13 as druggable cofactors in various cancers.Having developed inhibitors of these cofactors, we have found that certain altered gene expression programs confer unique vulnerabilities to transcription inhibitors.

Our recent accomplishments include:

  • Development of THZ1, a CDK7/12/13 inhibitor. THZ1 is a CDK7/12/13 inhibitor that leads to the preferential loss of expression of genes regulated by super-enhancers. THZ1 shows encouraging effects in pre-clinical models of T-cell acute lymphoblastic leukemia, neuroblastoma, and breast, lung, and bladder cancers.
  • Development of THZ531, a CDK12/13 inhibitor. Inhibition of CDK12, a major transcriptional regulator of DNA repair gene expression, can sensitize cancer cells to DNA damage. THZ531 synergizes with pharmacological inhibitors of PARP, a protein involved in DNA repair, leading to profound loss of tumor viability in cellular and in vivo models of Ewing Sarcoma.

↑ Back To Top

Drugging the Immune System

Immunotherapy is becoming a mainstay of cancer treatment. The most effective agents currently in use are antibodies that block receptors involved in immune evasion including PD-1, PDL1 and CTLA4. We have demonstrated that small molecule mediated targeting of intracellular proteins, such as CDK4/6, enhances the ability of the immune system to recognize and destroy tumor cells. We continue our efforts to discover additional intracellular targets in the context of immunooncology.

Our key insight in this area is:

  • CDK4/6 inhibitor (palbociclib) synergizes with anti-PD-1 blockade to enhance the anti-tumor immune response

↑ Back To Top

Tackling Challenging Drug Targets

Challenging Drug Targets: Mutant K-RAS is a frequent genetic alteration found in many cancers that is yet to be effectively drugged. We are exploring novel approaches to targeting mutant K-RAS using a guanosine diphosphate mimetic covalent inhibitor. We are also exploring the development of small molecule degraders of HER3, a catalytically inactive member of the EGFR-family that has been successfully drugged with antibodies but for which no small molecule antagonists are currently known.

Some examples of our work in this area are:

  • Development of SML-8-73-1, a covalent K-RAS inhibitor. SML covalently labels Cysteine 12 of the oncogenic K-RAS G12C mutant, and stabilizes the protein in an inactive form.
  • Initial development of a difluoromethylene bisphosphonate analog, XY-02-082. This compound provides a foundation for development of K-RAS targeting prodrugs with improved cellular uptake.
  • Hydrophobically-tagged covalent HER3 binders were developed. Ongoing work seeks to improve the potency of this novel class of inhibitors.

↑ Back To Top

Tools for Orphan Kinases

Despite intensive research efforts, much of the kinome is poorly annotated and incompletely understood. This ‘dark’ kinome represents a significant portion of the kinase space and an untapped targeting opportunity. We are developing a suite of approaches to tackle these understudied kinases including the development of selective inhibitors, tagging strategies for rapid degradation, and phosphoproteomics approaches to enable identification of kinase substrates.

Our efforts in this area include:

  • Development of the selective inhibitors of MELK and demonstrating the MELK inhibition, mRNA depletion or protein degradation does not inhibit proliferation of breast cancer cells.
  • Development of the first selective inhibitors of HIPK2.
  • Development of the first covalent inhibitors that target an active site tyrosine in the kinase SRPK1.

↑ Back To Top

New Approaches for Identifying and Optimizing Covalent Inhibitors

Covalent inhibitors have traditionally come from natural products (ie betalactams, aspirin) or from structure-based inhibitor design (ie covalent kinase inhibitors such as osimertinib). Recent advances in quantitative mass spectrometry are enabling proteome-wide surveys of thousands of proteins bearing reactive cysteines. We are developing procedures that incorporate covalent fragment screening coupled with structure-based inhibitor design to develop first-in-class covalent probes for previously difficult-to-drug targets. Two recently published examples are covalent PIN1 inhibitors (sulphopin) and covalent TEAD inhibitors.

↑ Back To Top

Covalent Kinase Inhibitors

Developing selective ATP-competitive kinase inhibitors can be challenging due to the highly conserved nature of the ATP binding site in the approximately 580 human kinases. We have worked to develop approaches for making selective kinase inhibitors that form a covalent bond with cysteine residues that are frequently found in and around the ATP-binding pocket. Covalent kinase inhibitors have the advantage of being able to combine selectivity obtained from non-covalent recognition of specific scaffold with careful positioning of a reactive group adjacent to a particular cysteine residue. Moreover, covalent inhibitors can achieve full target engagement in vivo often without the need for an extensive campaign to modulate the pharmacokinetic properties of the compound. For kinase inhibitors that are obligately covalent to achieve potency, mutation of the cysteine can provide a chemical-genetic method for proving that the observed pharmacology is ‘on-target’. Over the years, we have developed numerous selective covalent kinase inhibitors and have developed chemical proteomic methods for assessing their cellular selectivity.

↑ Back To Top